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Background: A large number of elderly, frail patients are exposed to polypharmacy, drug interactions and potentially inappropriate medication. Particular attention is paid to drugs with anticholinergic and sedative effects, which can lead to adverse health outcomes. The Drug Burden Index (DBI) is a [for full text, please go to the a.m. URL], 27. Jahrestagung der Gesellschaft für Arzneimittelanwendungsforschung und Arzneimittelepidemiologie

Background: Many multimorbid and frail older patients are exposed to polypharmacy, which increases the risk of adverse drug events and hospitalisation. Deprescribing medications, whose benefits no longer outweigh the risks, may reduce the rate of hospitalisations and adverse outcomes. A priorisation[for full text, please go to the a.m. URL], 26. Jahrestagung der Gesellschaft für Arzneimittelanwendungsforschung und Arzneimittelepidemiologie

Background: Despite a tremendous increase in prescribing of direct oral anticoagulants (DOACs) in recent years, limited data is available on prescribers’ adherence to registered indications (ICs), contraindications (CIs), special warnings/precautions (SW/PCs), and potential drug-drug[for full text, please go to the a.m. URL], 26. Jahrestagung der Gesellschaft für Arzneimittelanwendungsforschung und Arzneimittelepidemiologie

Neuropathic pain is a debilitating and commonly treatment-refractory condition requiring novel therapeutic options. Accumulating preclinical studies indicate that the potassium channel Slack (KNa1.1) contributes to the processing of neuropathic pain, and that Slack activators, when injected into mice, ameliorate pain-related hypersensitivity. However, whether Slack activation might reduce neuropathic pain in humans remains elusive. Here, we evaluated the tolerability and analgesic efficacy of loxapine, a first-generation antipsychotic drug and Slack activator, in neuropathic pain patients. We aimed to treat 12 patients with chronic chemotherapy-induced, treatment-refractory neuropathic pain (pain severity ≥ 4 units on an 11-point numerical rating scale) in a monocentric, open label, proof-of-principle study. Patients received loxapine orally as add-on analgesic in a dose-escalating manner (four treatment episodes for 14 days, daily dose: 20, 30, 40, or 60 mg loxapine) depending on tolerability and analgesic efficacy. Patient-reported outcomes of pain intensity and/or relief were recorded daily. After enrolling four patients, this study was prematurely terminated due to adverse events typically occurring with first-generation antipsychotic drugs that were reported by all patients. In two patients receiving loxapine for at least two treatment episodes, a clinically relevant analgesic effect was found at a daily dose of 20–30 mg of loxapine. Another two patients tolerated loxapine only for a few days. Together, our data further support the hypothesis that Slack activation might be a novel strategy for neuropathic pain therapy. However, loxapine is no valid treatment option for painful polyneuropathy due to profound dopamine and histamine receptor-related side effects. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02820519.

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

Objectives: The objective of the study was to develop and validate an adequate tool to evaluate the risk of bias of randomized controlled trials, observational studies, and systematic reviews assessing drug adverse events. Study Design and Setting: We developed a structured risk of bias checklist applicable to randomized trials, cohort, case control and nested case-control studies, and systematic reviews focusing on drug safety. Face and content validity was judged by three experienced reviewers. Interrater and intrarater reliability were determined using 20 randomly selected studies, assessed by three other independent reviewers including one performing a 3-week retest. Results: The developed checklist examines eight domains-study design and objectives, selection bias, attrition, adverse events information bias, other information bias, statistical methods to control confounding, other statistical methods, and conflicts of interest. The total number of questions varied from 10 to 32 depending on the study design. Interrater and intrarater agreements were fair with Kendall's W of 0.70 and 0.74, respectively. Median time to complete the checklist was 8.5 minutes. Conclusion: The developed checklist showed face and content validity and acceptable reliability to assess the risk of bias for studies analyzing drug adverse events. Hence, it might be considered as a novel useful tool for systematic reviews and meta-analyses focusing on drug safety. (C) 2017 Elsevier Inc. All rights reserved.

Purpose: Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence, calculated in a uniform manner, in seven European electronic healthcare databases. Methods: Annual prevalence per 10,000 person-years (PYs) was calculated for 2001-2009 in databases from Spain, Germany, Denmark, the United Kingdom (UK), and the Netherlands. Prevalence data were stratified according to age, sex, antidepressant type (selective serotonin re-uptake inhibitors [SSRIs] or tricyclic antidepressants [TCAs]) and major indications. Results: The age- and sex-standardized prevalence was lowest in the two Dutch (391 and 429 users per 10,000 PYs) and highest in the two UK (913 and 936 users per 10,000 PYs) populations in 2008. The prevalence in the Danish, German, and Spanish populations was 637, 618, and 644 users per 10,000 PY respectively. Antidepressants were prescribed most often in 20- to 60-year-olds in the two UK populations compared with the others. SSRIs were prescribed more often than TCAs in all except the German population. In the majority of countries we observed an increasing trend of antidepressant prescribing over time. Two different methods identifying recorded indications yielded different ranges of proportions of patients recorded with the specific indication (15-57 % and 39-69 % for depression respectively). Conclusion: Despite applying uniform methods, variations in the prevalence of antidepressant prescribing were obvious in the different populations. Database characteristics and clinical factors may both explain these variations. © 2014 Springer-Verlag.

Purpose: Results from observational studies on inhaled long-acting beta-2-agonists (LABA) and acute myocardial infarction (AMI) risk are conflicting, presumably due to variation in methodology. We aimed to evaluate the impact of applying a common study protocol on consistency of results in three databases. Methods: In the primary analysis, we included patients from two GP databases (Dutch—Mondriaan, UK—CPRD GOLD) with a diagnosis of asthma and/or COPD and at least one inhaled LABA or a “non-LABA inhaled bronchodilator medication” (short-acting beta-2-agonist or short-/long-acting muscarinic antagonist) prescription between 2002 and 2009. A claims database (USA—Clinformatics) was used for replication. LABA use was divided into current, recent (first 91 days following the end of a treatment episode), and past use (after more than 91 days following the end of a treatment episode). Adjusted hazard ratios (AMI-aHR) and 95 % confidence intervals (95 % CI) were estimated using time-dependent multivariable Cox regression models stratified by recorded diagnoses (asthma, COPD, or both asthma and COPD). Results: For asthma or COPD patients, no statistically significant AMI-aHRs (age- and sex-adjusted) were found in the primary analysis. For patients with both diagnoses, a decreased AMI-aHR was found for current vs. recent LABA use in the CPRD GOLD (0.78; 95 % CI 0.68–0.90) and in Mondriaan (0.55; 95 % CI 0.28–1.08), too. The replication study yielded similar results. Adjusting for concomitant medication use and comorbidities, in addition to age and sex, had little impact on the results. Conclusions: By using a common protocol, we observed similar results in the primary analysis performed in two GP databases and in the replication study in a claims database. Regarding differences between databases, a common protocol facilitates interpreting results due to minimized methodological variations. However, results of multinational comparative observational studies might be affected by bias not fully addressed by a common protocol.

Purpose: To assess the impact of a variety of methodological parameters on the association between six drug classes and five key adverse events in multiple databases. Methods: The selection of Drug-Adverse Event pairs was based on public health impact, regulatory relevance, and the possibility to study a broad range of methodological issues. Common protocols and data analytical specifications were jointly developed and independently and blindly executed in different databases in Europe with replications in the same and different databases. Results: The association between antibiotics and acute liver injury, benzodiazepines and hip fracture, antidepressants and hip fracture, inhaled long-acting beta2-agonists and acute myocardial infarction was consistent in direction across multiple designs, databases and methods to control for confounding. Some variation in magnitude of the associations was observed depending on design, exposure and outcome definitions, but none of the differences were statistically significant. The association between anti-epileptics and suicidality was inconsistent across the UK CPRD, Danish National registries and the French PGRx system. Calcium channel blockers were not associated with the risk of cancer in the UK CPRD, and this was consistent across different classes of calcium channel blockers, cumulative durations of use up to >10years and different types of cancer. Conclusions: A network for observational drug effect studies allowing the execution of common protocols in multiple databases was created. Increased consistency of findings across multiple designs and databases in different countries will increase confidence in findings from observational drug research and benefit/risk assessment of medicines.

Purpose: To assess the impact of a variety of methodological parameters on the association between six drug classes and five key adverse events in multiple databases. Methods: The selection of Drug-Adverse Event pairs was based on public health impact, regulatory relevance, and the possibility to study a broad range of methodological issues. Common protocols and data analytical specifications were jointly developed and independently and blindly executed in different databases in Europe with replications in the same and different databases. Results: The association between antibiotics and acute liver injury, benzodiazepines and hip fracture, antidepressants and hip fracture, inhaled long-acting beta2-agonists and acute myocardial infarction was consistent in direction across multiple designs, databases and methods to control for confounding. Some variation in magnitude of the associations was observed depending on design, exposure and outcome definitions, but none of the differences were statistically significant. The association between anti-epileptics and suicidality was inconsistent across the UK CPRD, Danish National registries and the French PGRx system. Calcium channel blockers were not associated with the risk of cancer in the UK CPRD, and this was consistent across different classes of calcium channel blockers, cumulative durations of use up to >10years and different types of cancer. Conclusions: A network for observational drug effect studies allowing the execution of common protocols in multiple databases was created. Increased consistency of findings across multiple designs and databases in different countries will increase confidence in findings from observational drug research and benefit/risk assessment of medicines.

Aim: Two inhaler devices (Respimat (R) and HandiHaler (R)) are available for tiotropium, a long acting anticholinergic agent. We aimed to analyze drug utilization, off-label usage and generalizability of the TIOSPIR trial results for both devices. MethodsPatients aged 18years exhibiting at least one documented prescription of tiotropium in the database of the Association of Statutory Health Insurance Physicians, Bavaria, Germany, were included (years 2004-2008). Annual period prevalence rates (PPRs) were calculated stratified by age, gender and inhaler devices. Off-label usage (patients lacking a chronic obstructive pulmonary disease (COPD) diagnosis) and the proportion of patients meeting the inclusion and exclusion criteria of the TIOSPIR trial were analyzed. ResultsBetween 2004 and 2008, PPRs increased and varied between 49.2 and 74.5 per 10000 persons for HandiHaler (R) and between 1.5 and 9.3 per 10000 persons for Respimat (R). Small differences regarding patient characteristics existed between the two inhaler devices. Only about 30% (HandiHaler (R) 32.1%, Respimat (R) 30.0%) of the database patients receiving tiotropium could be theoretically included in the TIOSPIR trial. ConclusionsComparing the two tiotropium devices, no clinically relevant differences regarding patient and prescribing characteristics were revealed. Results of the TIOSPIR trial were generalizable only to a minority of our study patients, underlining the need for real-life data.

BACKGROUND: For patients with asthma, COPD, or asthma-COPD overlap syndrome (ACOS), inter-country comparisons of seasonal changes in drug prescriptions are scarce or missing. Hence, we aimed to compare seasonal changes in prescription rates of long-acting beta-2-agonist (LABA) in four European countries. METHODS: A common study protocol was applied to six health care databases (Germany, Spain, the Netherlands (2), and the UK (2)) to calculate age- and sex-standardized point prevalence rates (PPRs) of LABA-containing prescriptions by the 1st of March, June, September, and December of each year during the study period 2002-2009. Seasonal variation of PPRs was quantified using seasonal indexes (SIs; based on the ratio-to-moving-average-method) and SIs averaged over the study period (aSI) stratified by sex, age, and indication (asthma, COPD, or ACOS). RESULTS: There was a moderate seasonal change in LABA-containing prescriptions which was more pronounced in asthma or COPD patients compared to ACOS patients. For asthma and ACOS patients, highest seasonal variation was found for patients living in Spain (aSI: 87.3-110.7, aSI: 93.2-103.1) whereas for COPD highest seasonal variation was revealed for the NPCRD database (the Netherlands) (aSI: 92.2-105.6). Regarding age and sex, highest seasonal variation was found in Spanish boys under 10 years of age having a diagnosis of asthma. CONCLUSIONS: By applying a common analysis in six databases, we could observe moderate overall seasonal changes in LABA-containing prescription rates in patients with asthma, COPD, or ACOS.

Background: For patients with asthma, COPD, or asthma-COPD overlap syndrome (ACOS), inter-country comparisons of seasonal changes in drug prescriptions are scarce or missing. Hence, we aimed to compare seasonal changes in prescription rates of long-acting beta-2-agonist (LABA) in four European countries. Methods: A common study protocol was applied to six health care databases (Germany, Spain, the Netherlands (2), and the UK (2)) to calculate age- and sex-standardized point prevalence rates (PPRs) of LABA-containing prescriptions by the 1st of March, June, September, and December of each year during the study period 2002e2009. Seasonal variation of PPRs was quantified using seasonal indexes (SIs; based on the ratio-to-moving-average-method) and SIs averaged over the study period (aSI) stratified by sex, age, and indication (asthma, COPD, or ACOS). Results: There was a moderate seasonal change in LABA-containing prescriptions which was more pronounced in asthma or COPD patients compared to ACOS patients. For asthma and ACOS patients, highest seasonal variation was found for patients living in Spain (aSI: 87.3e110.7, aSI: 93.2e103.1) whereas for COPD highest seasonal variation was revealed for the NPCRD database (the Netherlands) (aSI: 92.2e105.6). Regarding age and sex, highest seasonal variation was found in Spanish boys under 10 years of age having a diagnosis of asthma. Conclusions: By applying a common analysis in six databases, we could observe moderate overall seasonal changes in LABA-containing prescription rates in patients with asthma, COPD, or ACOS.

Background and aim: Preventability of adverse drug reactions (ADRs) is a matter of public concern and usually evaluated using pre-defined questions and algorithms. Assessment of preventability of ADRs is characterised by a significant inter-rater variability (IRV). Within the German Network of Regional[for full text, please go to the a.m. URL], 16. Jahrestagung der Gesellschaft für Arzneimittelanwendungsforschung und Arzneimittelepidemiologie

Background and aim: Certain drugs are classified as potentially inappropriate medication (PIM) for elderly patients due to their increased risk for causing adverse drug reactions [Laroche ML et al. 2009]. Since published international PIM lists may not be suitable for Germany, we are developing[for full text, please go to the a.m. URL], 16. Jahrestagung der Gesellschaft für Arzneimittelanwendungsforschung und Arzneimittelepidemiologie

Objective: To report 3 cases of nephrogenic systemic fibrosis (NSF) focussing on the time course of clinical symptoms after exposure to gadolinium based contrast agents (GBCA) and to discuss pharmacokinetic aspects of commercially available GBCA. Patients' details: All 3 patients (2 men, 1 woman, aged 51 - 54 years) suffered from end-stage renal disease (ESRD) and were on long-term dialysis. Linear GBCA compounds were given to all patients and NSF symptoms started 6 months, 1 and 4 years after the last GBCA exposure. In 2 patients, GBCA was administered after the occurrence of (unrecognized) NSF symptoms leading to worsening of clinical courses. 1 of the patients received multiple therapies (e.g. UV-A1 treatment, physical therapy) without significant improvement, 2 patients died from cardiac complications shortly after the diagnosis of NSF. Conclusion: NSF may develop after a longer period of time than generally reported and GBCA administration may aggravate or accelerate chronic, subclinical NSF symptoms.

Hip fractures represent a major public health challenge worldwide. Multinational studies using a common methodology are scarce. We aimed to estimate the incidence rates (IRs) and trends of hip/femur fractures over the period 2003-2009 in five European countries. The study was performed using seven electronic health-care records databases (DBs) from Denmark, The Netherlands, Germany, Spain, and the United Kingdom, based on the same protocol. Yearly IRs of hip/femur fractures were calculated for the general population and for those aged a parts per thousand yen50 years. Trends over time were evaluated using linear regression analysis for both crude and standardized IRs. Sex- and age-standardized IRs for the UK, Netherlands, and Spanish DBs varied from 9 to 11 per 10,000 person-years for the general population and from 22 to 26 for those a parts per thousand yen50 years old; the German DB showed slightly higher IRs (about 13 and 30, respectively), whereas the Danish DB yielded IRs twofold higher (19 and 52, respectively). IRs increased exponentially with age in both sexes. The ratio of females to males was a parts per thousand yen2 for patients aged a parts per thousand yen70-79 years in most DBs. Statistically significant trends over time were only shown for the UK DB (CPRD) (+0.7 % per year, P < 0.01) and the Danish DB (-1.4 % per year, P < 0.01). IRs of hip/femur fractures varied greatly across European countries. With the exception of Denmark, no decreasing trend was observed over the study period.

Anticoagulants; Europe; Non valvular atrial fibrillation Anticoagulants; Europa; Fibril·lació auricular no valvular Anticoagulantes; Europa; Fibrilación auricular no valvular Aims: To describe and compare the adherence to different direct oral anticoagulants (DOACs) in eight European databases representing six countries. Methods: Longitudinal drug utilization study of new users (≥18 years) of DOACs (dabigatran, rivaroxaban, apixaban) with a diagnosis of non-valvular atrial fibrillation (2008–2015). Adherence was examined by estimating persistence, switching, and discontinuation rates at 12 months. Primary non-adherence was estimated in BIFAP and SIDIAP databases. Results: The highest persistence rate was seen for apixaban in the CPRD database (81%) and the lowest for dabigatran in the Mondriaan database (22%). The switching rate for all DOACs ranged from 2.4 to 13.1% (Mondriaan and EGB databases, respectively). Dabigatran had the highest switching rate from 5.0 to 20.0% (Mondriaan and EGB databases, respectively). The discontinuation rate for all DOACs ranged from 16.0 to 63.9% (CPRD and Bavarian CD databases, respectively). Dabigatran had the highest rate of discontinuers, except in the Bavarian CD and AOK NORDWEST databases, ranging from 23.2 to 64.6% (CPRD and Mondriaan databases, respectively). Combined primary non-adherence for examined DOACs was 11.1% in BIFAP and 14.0% in SIDIAP. There were differences in population coverage and in the type of drug data source among the databases. Conclusion: Despite the differences in the characteristics of the databases and in demographic and baseline characteristics of the included population that could explain some of the observed discrepancies, we can observe a similar pattern throughout the databases. Apixaban was the DOAC with the highest persistence. Dabigatran had the highest proportion of discontinuers and switchers at 12 months in most databases (EMA/2015/27/PH). The project has received support from the European Medicines Agency under the Framework service contract (nr EMA/2015/27/PH) with regard to the reopening of competition no. 3. K. Janhsen (Witten/Herdecke University, Alfred-Herrhausen-Straße 50, 58448 Witten, Germany (UW/GH)) and A. Heeke (AOK NORDWEST, Kopenhagener Straße 1, 44269 Dortmund, Germany). R. Gerlach and M. Tauscher (National Association of Statutory Health Insurance Physicians of Bavaria, Elsenheimerstr. 39, MD-80687 Munich, Germany). The authors from the BIFAP database would like to acknowledge the excellent collaboration of the primary care general practitioners and pediatricians, and also the support of the regional governments to the database. This study is based in part on data from the ‘base de datos para la investigación Farmacoepidemiológica en Atención Primaria’ (BIFAP) fully financed by the Spanish Agency on Medicines and Medical Devices (AEMPS). The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the EMA (European Medicines Agency) or one of its committees or working parties, or AEMPS (Agencia Española de Medicamentos y Productos Sanitarios). The authors thank Alethea Charlton for her support reviewing and editing the English. The authors thank SIDIAP (Sistema d’informació per al Desenvolupament de Investigació en Atenció Primària) for providing the data with respect to CPRD, approval of the study protocol was granted by the Independent Scientific Advisory Committee of the Medicines and Healthcare Products Regulatory Agency (protocol 17_089R).