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Background: There is growing interest in the use of electronic healthcare records (EHR) databases for drug safety signal detection, but an important concern is whether these databases have the data and adequate power to monitor all types of drugs and all types of adverse events. Objectives: To put into perspective expectations about use of EHR data-based systems as new approach to signal detection and active drug safety surveillance. Methods: Within the setting of EU-ADR network comprising eight European EHR databases (administrative claims and general practice medical records) and in the context of a cohort study, we determined the amount of drug exposure required to enable detection of safety signals of varying magnitudes of risk. We provide estimates of the number and types of drugs (WHO ATC Classification, 5th level) that can be monitored as a function of actual use, minimal detectable relative risk (RR), and empirically-derived Background incidence rates of the following adverse events deemed to be important in pharmacovigilance: (1) acute myocardial infarction; (2) acute renal failure; (3) anaphylactic shock; (4) bullous eruptions; (5) rhabdomyolysis; and (6) upper gastrointestinal bleeding.[1] We further perform data simulation in an attempt to see if, and how, expansion of database size would make a difference in the capabilities of the system. Results: Data from 19 647 452 individuals (59 594 132 person-years follow-up) who used 2289 drugs 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 and 939 drugs (41%) for which an association with RR= 4 can be investigated. For a rare event such as rhabdomyolysis there are 19 drugs (1%) for which an association with RR= 2, if present, can be investigated and 170 drugs (7%) for which an association with RR= 4 can be investigated. With expansion of the database network to 10 times its current size (»200 million subjects) the percentage of drugs that can be monitored for acute myocardial infarction may increase to 44% (at RR= 2) and for rhabdomyolysis to 23% (at RR= 4). Conclusions: Drug safety signal detection using linked healthcare data-based networks for signal detection is feasible, although the leverage to do so may be low for drugs that are infrequently used and for very rare events. Extending the database network size to include data from more heterogeneous populations and increasing followup time are warranted to maximize the leverage of these surveillance systems.

AIM. The Biphosphonates Efficacy-Safety Tradeoff (BEST) study was designed to evaluate efficacy and safety of oral BP in primary care. METHODS. Hospital discharges and pharmacy claims, collected over a population of 19 million enrolees in the Italian National Health System, were used to select records of subjects aged 55+ years, discharged from hospital with a primary diagnosis of fracture at osteoporotic sites. Exclusion criteria included cancer, Paget disease, and previous BP use. Post-discharge prescription of oral BP was recorded. Outcomes of the BEST study are: 1) occurrence of osteonecrosis of the jaw (ONJ), 2) gastro-intestinal bleeding, and 3) recurrent fracture. Data on BP utilization and ICD9CM-based diagnoses of ONJ are currently available. RESULTS. Out of 72,675 eligible subjects (mean age: 67 years; 71% females), 11% (females: 16%, males: 6%; p

Objective: To explore the association between dopamine agonists (DAs) and cardiac valve regurgitation (CVR) or pleural/pulmonary/pericardial/retroperitoneal fibroses in patients with Parkinson’s disease (PD). Background: There is increasing evidence on ergot DA-induced cardiac valve fibrosis (i.e. regurgitation) in PD patients while the association between DA use and other fibroses is still unclear. Methods: A nested case control study was conducted in a cohort of PD patients who were newly treated with DAs or Levodopa. Study patients were identified from over 6 million persons in THIN (UK), Health Search-Thales (Italy), and IPCI (NL) general practice databases. Cases of CVR and fibroses were validated by manual review of medical records and specialist letters. Controls were matched to cases on age, gender, index date and database. Relative risks and 95% confidence intervals (CI) of CVR and fibroses were calculated for different DAs, compared to levodopa. Results: In the study cohort of 19,656 PD patients (7,890 DA users, 11,766 levodopa users), 85 incident cases of CVR were identified during follow-up. Compared to levodopa, only cabergoline was associated with significantly increased risk of CVR (OR:4.6; 95%CI:2.4-8.8). The risk was statistically significant after 6 months of therapy (OR:7.4; 95%CI:3.7-15.0) and was highest in those patients switching from pergolide (OR:60.7; 95%CI:12-308) and after the first specific safety warning in 2004 (OR:5.1; 95%CI:2.5-10.5). There was no association between any DA and other fibroses (N.cases513). Conclusions: Increased risk of CVR was observed only in PD patients using cabergoline for more than 6 months. Detection bias and previous exposure to pergolide may partly account for this risk. No increase in the risk of other fibroses for any DA was found.

Objective: To demonstrate the value of combining data from multiple databases to address urgent safety issues, such as the risk of cardiac valve fibrosis with dopamine agonist use. Background: To explore the association between rare exposures and outcomes, a single automated database may not provide sufficient sample size and heterogeneity of exposure needed for comparative pharmacoepidemiologic drug safety research. Methods: Cohorts of new users of either 1) DAs or 2) levodopa, and 3) database, gender and age-matched controls from general population were identified from THIN-UK, Italian HSD-THALES, Dutch-IPCI GP databases, and Dutch-PHARMO record linkage system between 1996 and 2007. After database-specific extractions using common data model, a unique output dataset was created. Results: During the study period, cohorts identified were: 1) DA users for PD (N510,790) or hyperprolactinemia (N58,386), 2) levodopa (N514,669), and 3) controls (N529,311). Statistically significant differences on DA use were observed among Countries. Overall, cabergoline was the most frequently used DA (43%), irrespective of indication of use, with highest use in Italy (47%) and lowest use in UK (22%). Non-ergot DAs had the highest use in UK (35%) and NL (25%) and lowest use in Italy (18%). Conclusions: Combining data from multiple databases increases study size and heterogeneity of exposure, which can facilitate drug comparisons.

Background: With rare exposures and outcomes, a single automated database may not provide sufficient subjects and heterogeneity of exposure needed for comparative pharmacoepidemiologic drug safety research. Objectives: Data from 4 general practitioner (GP) databases and record linkage systems in 3 European countries were combined to assess the association between individual dopamine agonists (DA) and cardiopulmonary disorders. The objective of this abstract is to demonstrate the value of combining data from multiple databases to address potential safety issues. Methods: Four cohorts of 1) new users of DAs for Parkinson’s disease (PD) or hyperprolactinemia, 2) levodopa, 3) DA-naive persons with hyperprolactinemia, and 4) database, gender and age-matched controls were identified from THIN-UK, Italian HSD-THALES, Dutch-IPCI GP databases, and the Dutch-PHARMO record linkage system between 1996–2007. Outcomes were identified by automated and medical record abstraction after mapping of codes, and validated by an expert panel blinded to exposure. After database-specific extractions, a common output dataset was created. Results: During the study period, cohorts identified were 1) DA users for PD or hyperprolactinemia (>35,000), 2) levodopa (18,000), 3) DA-naive persons with hyperprolactinemia (16,000) and 4) controls (>35,000). Overall, cabergoline was the most frequently used DA (42%), with highest use in Italy (48%) and lowest use in UK (16%). Non-ergot DAs had the highest use in UK (35%) and NL (25%) and lowest use in Italy (18%). Apomorphine was the most frequently used non-ergot DA in UK (25%). Conclusions: Combining data from multiple databases increases study size, generalizability, and heterogeneity of exposure, which can facilitate drug comparisons.

Background Data on the effect of oral bisphosphonates (BPs) on risk of upper gastrointestinal complications (UGIC) are conflicting. We conducted a large population-based study from a network of Italian healthcare utilization databases aimed to assess the UGIC risk associated with use of BPs in the setting of secondary prevention of osteoporotic fractures. Methods A nested case–control study was carried out within a cohort of 68,970 patients aged 45 years or older, who have been hospitalized for osteoporotic fracture from 2003 until 2005. Cases were the 804 patients who experienced hospitalization for UGIC until 2007. Up to 20 controls were randomly selected for each case. Conditional logistic regression model was used to estimate odds ratio (OR) associated with current and past use of BPs (i.e. for drug dispensation within 30 days and over 31 days prior the outcome onset, respectively) after adjusting for several covariates. Results Compared with patients who did not use BPs, current and past users had OR (and 95% confidence interval) of 0.86 (0.60 to 1.22) and 1.07 (0.80 to 1.44) respectively. There was no difference in the ORs estimated according with BPs type (alendronate or risedronate) and regimen (daily or weekly), nor with co-therapies and comorbidities. Conclusions Further evidence that BPs dispensed for secondary prevention of osteoporotic fractures are not associated with increased risk of severe gastrointestinal complications is supplied from this study. Further research is required to clarify the role BPs and other drugs of co-medication in inducing UGIC.

BSNC werkt nadrukkelijk mee aan een duurzame aanpak. Los van de juridische haalbaarheid ondersteunt BSNC de conclusie dat een absoluut verbod op gebruik van gewasbeschermingsmiddelen op sportvelden in 2017 niet haalbaar is. Zorgvuldig gebruik van gewasbeschermingsmiddelen is en blijft noodzakelijk. Op basis van IPM kan men in 2015 de concreet haalbare reductie op de milieudruk voor sportvelden vastleggen. De milieubelasting richt zich op volume en effect op water, leven, bodemleven, grondwater en de mate van vervluchtiging.

Background: Most NSAIDs are thought to be able to cause hepatic injury and acute liver failure (ALF), but the event rates of those leading to transplantation (ALFT) remain uncertain. Objectives: The aim of the study was to estimate population event rates for NSAID-associated ALFT Methods: This was a case-population study of ALFT in 57 eligible liver transplant centres in seven countries (France, Greece, Ireland, Italy, The Netherlands, Portugal and the UK). Cases were all adults registered from 2005 to 2007 for a liver transplant following ALFT without identified clinical aetiology, exposed to an NSAID or paracetamol (acetaminophen) within 30 days before the onset of clinical symptoms. NSAID and paracetamol population exposures were assessed using national sales data from Intercontinental Marketing Services (IMS). Risk was estimated as the rate of ALFT per million treatment-years (MTY). Results: In the 52 participating centres, 9479 patients were registered for transplantation, with 600 for ALFT, 301 of whom, without clinical aetiology, had been exposed to a drug within 30 days. Of these 301 patients, 40 had been exposed to an NSAID and 192 to paracetamol (81 of whom were without overdose). Event rates per MTY were 1.59 (95 % CI 1.1-2.2) for all NSAIDs pooled, 2.3 (95 % CI 1.2-3.9) for ibuprofen, 1.9 (95 % CI 0.8-3.7) for nimesulide, 1.6 (95 % CI 0.6-3.4) for diclofenac and 1.6 (95 % CI 0.3-4.5) for ketoprofen. For paracetamol, the event rate was 3.3 per MTY (95 % CI 2.6-4.1) without overdoses and 7.8 (95 % CI 6.8-9.0) including overdoses. Conclusions: ALF leading to registration for transplantation after exposure to an NSAID was rare, with no major difference between NSAID. Non-overdose paracetamol-exposed liver failure was twice more common than NSAID-exposed liver failure. © 2013 The Author(s).

Aim In the last decade, new glucose lowering drugs (GLDs) have been launched, and also several warnings regarding their safety. The cardiovascular safety of thiazolidinediones (TZD) has been questioned. We analyzed the prescription pattern of GLDs from 2000 to November 2009 in the United Kingdom (UK) using the THIN database with special focus on the effects of the safety warnings about rosiglitazone issued in May 2007 and January 2008. Methods Annual prevalence and incidence of GLD prescriptions were measured. For TZD, the monthly prevalence and incidence of prescription were calculated from May 2006 to January 2009. The switching pattern around the FDA alert and the characteristics of subjects starting treatment with TZD before and after the alerts were observed. Results The prevalence of prescriptions of GLDs increased during the 10year period, metformin increasing more than three times. Rosiglitazone prevalence showed an increased trend until May 2007, (2.3/ 1000 person-years) and decreased thereafter (January 2009: 1.1/1000 person-years). The use of pioglitazone increased surpassing rosiglitazone from April 2008 onwards. The incidence of rosiglitazone use decreased sharply after May 2007 (0.8/1000 person-years). The prevalence of use of other therapies remained rather stable from 2000 to 2007 but increased afterwards. After May 2007, rosiglitazone users were increasingly switched to pioglitazone. There was an increased proportion of new users of pioglitazone with cardiovascular risk after the alerts. Conclusions The prescription of GLDs in the UK has increased in the last decade. For TZDs, it changed after May 2007 as well as the characteristics of the subjects treated with them.

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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 1,947,452 individuals (59,594,132 person-years follow-up) who used 2,289 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 rare event such as rhabdomyolysis, there are 19 drugs (1%) for which an association of same magnitude can be 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.

The EU-ADR project aims to exploit different European electronic healthcare records (EHR) databases for drug safety signal detection. In this paper we report the preliminary results concerning the comparison of signal detection between EU-ADR network and two spontaneous reporting databases, the Food and Drug Administration and World Health Organization databases. EU-ADR data sources consist of eight databases in four countries (Denmark, Italy, Netherlands, and United Kingdom) that are virtually linked through distributed data network. A custom-built software (Jerboa©) elaborates harmonized input data that are produced locally and generates aggregated data which are then stored in a central repository. Those data are subsequently analyzed through different statistics (i.e. Longitudinal Gamma Poisson Shrinker). As potential signals, all the drugs that are associated to six events of interest (bullous eruptions - BE, acute renal failure - ARF, acute myocardial infarction - AMI, anaphylactic shock - AS, rhabdomyolysis - RHABD, and upper gastrointestinal bleeding - UGIB) have been detected via different data mining techniques in the two systems. Subsequently a comparison concerning the number of drugs that could be investigated and the potential signals detected for each event in the spontaneous reporting systems (SRSs) and EU-ADR network was made. SRSs could explore, as potential signals, a larger number of drugs for the six events, in comparison to EU-ADR (range: 630-3,393 vs. 87-856), particularly for those events commonly thought to be potentially drug-induced (i.e. BE: 3,393 vs. 228). The highest proportion of signals detected in SRSs was found for BE, ARF and AS, while for ARF, and UGIB in EU-ADR. In conclusion, it seems that EU-ADR longitudinal database network may complement traditional spontaneous reporting system for signal detection, especially for those adverse events that are frequent in general population and are not commonly thought to be drug-induced. The methodology for signal detection in EU-ADR is still under development and testing phase.

Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with approximately 832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 x 10(-12)), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 x 10(-9)) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 x 10(-9)). We also confirmed prior associations near SOX17 (8q11.23-q12.1; OR = 1.28, P = 1.3 x 10(-12)) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 x 10(-22)). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.

The overall objective of the EU-ADR project is the design, development, and validation of a computerised system that exploits data from electronic health records and biomedical databases for the early detection of adverse drug reactions. Eight different databases, containing health records of more than 30 million European citizens, are involved in the project. Unique queries cannot be performed across different databases because of their heterogeneity: Medical record and Claims databases, four different terminologies for coding diagnoses, and two languages for the information described in free text. The aim of our study was to provide database owners with a common basis for the construction of their queries. Using the UMLS, we provided a list of medical concepts, with their corresponding terms and codes in the four terminologies, which should be considered to retrieve the relevant information for the events of interest from the databases.

The overall objective of the eu-ADR project is the design, development, and validation of a computerised system that exploits data from electronic health records and biomedical databases for the early detection of adverse drug reactions. Eight different databases, containing health records of more than 30 million European citizens, are involved in the project. Unique queries cannot be performed across different databases because of their heterogeneity: Medical record and Claims databases, four different terminologies for coding diagnoses, and two languages for the information described in free text. The aim of our study was to provide database owners with a common basis for the construction of their queries. Using the UMLS, we provided a list of medical concepts, with their corresponding terms and codes in the four terminologies, which should be considered to retrieve the relevant information for the events of interest from the databases.