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Background: The socioeconomic status is often an important confounder in the context of epidemiological studies. However, this information is typically not included in studies based on claims data, possibly due to a lack of knowledge regarding the completeness and validity of the available information.Objectives: Our aim was to assess and evaluate the socioeconomic status in the German Pharmacoepidemiological Research Database (GePaRD).Methodology: First, an algorithm was developed to assign an educational status to individuals insured in 2017 in order to estimate the socioeconomic status at the individual level. For comparison, the socioeconomic status was estimated based on the place of residence. For plausibility, we examined whether the known association between the presence of obesity and the socioeconomic status could be reproduced.Results: Based on different age groups it was possible to dichotomously estimate the socioeconomic status for 86–93% of those under 60 years of age and for 67% of the 60- to 69-year-olds. For individuals 70 years and older, the proportion of missing values was very high. In all subgroups, the prevalence of obesity was higher among persons of lower socioeconomic status than among persons of higher socioeconomic status. The estimation based on the place of residence produced plausible results, but with smaller differences by socioeconomic status.Discussion and conclusion: Overall, the study results suggest that in terms of plausibility and completeness the information available in GePaRD is well suited for estimating the individual socioeconomic status for age groups up to 69 years.

Introduction: Pharmacovigilance is vital for drug safety. The process typically involves two key steps: initial signal generation from spontaneous reporting systems (SRSs) and subsequent expert review to assess the signals' (potential) causality and decide on the appropriate action. Methods: We propose a novel discovery and verification approach to pharmacovigilance based on electronic healthcare data. We enhance the signal detection phase by introducing an ensemble of methods which generated signals are combined using Borda count ranking; a method designed to emphasize consensus. Ensemble methods tend to perform better when data is noisy and leverage the strengths of individual classifiers, while trying to mitigate some of their limitations. Additionally, we offer the committee of medical experts with the option to perform an in-depth investigation of selected signals through tailored pharmacoepidemiological studies to evaluate their plausibility or spuriousness. To illustrate our approach, we utilize data from the German Pharmacoepidemiological Research Database, focusing on drug reactions to the direct oral anticoagulant rivaroxaban. Results: In this example, the ensemble method is built upon the Bayesian confidence propagation neural network, longitudinal Gamma Poisson shrinker, penalized regression and random forests. We also conduct a pharmacoepidemiological verification study in the form of a nested active comparator case-control study, involving patients diagnosed with atrial fibrillation who initiated anticoagulant treatment between 2011 and 2017. Discussion: The case study reveals our ability to detect known adverse drug reactions and discover new signals. Importantly, the ensemble method is computationally efficient. Hasty false conclusions can be avoided by a verification study, which is, however, time-consuming to carry out. We provide an online tool for easy application: https://borda.bips.eu. [ABSTRACT FROM AUTHOR]

Background: The European rivaroxaban post-authorization safety study evaluated bleeding risk among patients initiated on rivaroxaban or vitamin K antagonists for the treatment and secondary prevention of venous thromboembolism in routine clinical practice. Methods: Cohorts were created using electronic healthcare databases from the UK, the Netherlands, Germany and Sweden. Patients with a first prescription of rivaroxaban or vitamin K antagonist during the period from December 2011 (in the UK, January 2012) to December 2017 (in Germany, December 2016) for venous thromboembolism indication, with no record of atrial fibrillation or recent cancer history, were observed until the occurrence of each safety outcome (hospitalization for intracranial, gastrointestinal, urogenital or other bleeding), death or study end (December 2018; in Germany, December 2017). Crude incidence rates of each outcome per 100 person-years were computed. Results: Overall, 44 737 rivaroxaban and 45 842 vitamin K antagonist patients were enrolled, mean age, 59.9–63.8 years. Incidence rates were similar between rivaroxaban and vitamin K antagonist users with some exceptions, including higher incidence rates for gastrointestinal bleeding in rivaroxaban users than in vitamin K antagonist users. Among rivaroxaban users, mortality and bleeding risk generally increased with age, renal impairment and diabetes. Conclusions: This study provides further data from routine clinical practice that broadly support safety profile of rivaroxaban for VTE indication and complement findings from previous randomized clinical trials. [ABSTRACT FROM AUTHOR]

Aims Atrial fibrillation (AF) is a risk factor for brain infarction, which can lead to epilepsy. We aimed to investigate whether treatment of AF with direct oral anticoagulants (DOACs) affects the risk of epilepsy in comparison to treatment with the vitamin K antagonist phenprocoumon (PPC). Methods and results We performed an active comparator, nested case-control study based on the German Pharmacoepidemiological Research Database that includes claims data from statutory health insurance providers of about 25 million persons since 2004. In 2011–17, 227 707 AF patients initiated treatment with a DOAC or PPC, of which 1828 cases developed epilepsy on current treatment with an oral anticoagulant. They were matched to 19 084 controls without epilepsy. Patients with DOAC treatment for AF had an overall higher risk of epilepsy with an odds ratio of 1.39, 95% CI (1.24; 1.55) compared to current PPC treatment. Cases had higher baseline CHA2DS2-VASc scores and more frequently a history of stroke than controls. After excluding patients with ischaemic stroke prior to the diagnosis of epilepsy, the risk of epilepsy was still higher on DOACs than on PPC. In contrast, within a cohort of patients with venous thromboembolism, the risk of epilepsy on treatment with DOACs was less elevated [adjusted odds ratio 1.15, 95% CI (0.98; 1.34)]. Conclusion In patients with AF initiating oral anticoagulation, treatment with a DOAC was associated with an increased risk of epilepsy compared to the vitamin K antagonist PPC. Covert brain infarction may explain the observed elevated risk of epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: Large health‐care databases are increasingly used for research on drug utilization and safety in pregnancy. For the German Pharmacoepidemiological Research Database (GePaRD), covering ~20% of the German population, algorithms have been developed to identify pregnancies, to estimate their date of onset and to link mothers to their babies. Using this methodology, we aimed to conduct a proof‐of‐concept analysis on the known association between valproate (VPA) exposure in early pregnancy and spina bifida in the exposed child. Methods: We identified all pregnancies in GePaRD between 2006 and 2016 in women aged 12 to 50 years. To each VPA dispensation of these women, an exposure period was assigned, based on the dispensation date and the number of defined daily doses in the dispensed package. A pregnancy was classified as exposed to VPA in the critical time window if this exposure period overlapped with the first 55 days of pregnancy. Risk ratios were calculated for spina bifida in live births and induced abortions comparing VPA‐exposed ones to all pregnancies. Results: Overall, we identified 1 271 384 pregnancies fulfilling the inclusion criteria. Of these, 668 pregnancies (0.053%) were classified as exposed to VPA in the critical time window regarding spina bifida. An induced abortion accompanied by a diagnosis of spina bifida was observed in one of the VPA‐exposed pregnancies (0.15%) and in 154 of all pregnancies (0.012%), yielding a risk ratio of 12.4 (95% confidence interval [CI]: 1.7–88.2). Out of 775 875 pregnancies ending in a live birth, 366 (0.047%) were classified as VPA exposed. A diagnosis of spina bifida was coded in 3 of 366 VPA‐exposed live births (0.82%) and in 260 of all live births (0.03%), yielding a relative risk of 24.5 (95% CI: 7.9–76.0). Conclusions: Our proof‐of‐concept analysis based on GePaRD showed a strong association between intrauterine exposure to VPA and occurrence of spina bifida. The results are plausible and consistent with the literature, supporting the suitability of GePaRD and the developed algorithms to conduct studies on drug safety in pregnancy. [ABSTRACT FROM AUTHOR]

Objective: To compare the risk of venous thromboembolism (VTE) among young women for nine combined oral contraceptives (COCs), including progestogens with an as yet unclear risk of VTE such as chlormadinone and nomegestrol, using COCs containing levonorgestrel with low ethinylestradiol (<50 μg) as a reference. Design: Case–control study nested in a cohort of new users of COCs. Setting German claims data. Population A total of 1166 cases of VTE matched to 11 660 controls nested in a cohort of 677 331 girls and young women aged 10–19 years with one or more COCs dispensed between 2005 and 2017 after a 1‐year period without any COCs. Methods: Confounder‐adjusted odds ratios (aORs) of VTE associated with current use of the respective COCs were calculated using conditional logistic regression. Main outcome measures: Venous thromboembolism (VTE), defined as a diagnosis of pulmonary embolism or deep vein thrombosis. Results: Compared with levonorgestrel with low ethinylestradiol (<50 μg), the risk of VTE was increased two‐fold for COCs containing dienogest (aOR 2.23, 95% CI 1.77–2.80), cyproterone (aOR 2.15, 95% CI 1.43–3.25), chlormadinone (aOR 2.06, 95% CI 1.58–2.68), desogestrel (aOR 1.93, 95% CI 1.44–2.61) and drospirenone (aOR 1.89, 95% CI 1.41–2.55), and increased five‐fold for gestodene (aOR 5.05, 95% CI 1.23–20.74). For norgestimate and nomegestrol, the point estimates suggest a two‐fold increased risk (aOR 1.90, 95% CI 0.62–5.81) and 40% increased risk (aOR 1.41, 95% CI 0.52–3.81), respectively. Conclusions: Our study confirms that levonorgestrel with low ethinylestradiol (<50 μg) is the COC associated with the lowest risk of VTE and suggests that for chlormadinone the risk of VTE is two times higher, and thus in the same range as for desogestrel and drospirenone. [ABSTRACT FROM AUTHOR]

Purpose: Validation of outcomes allows measurement of and correction for potential misclassification and targeted adjustment of algorithms for case definition. The purpose of our study was to validate algorithms for identifying cases of acute myocardial infarction (AMI), stroke, and cardiovascular (CV) death using patient profiles, ie, chronological tabular summaries of relevant available information on a patient, extracted from pseudonymized German claims data. Patients and Methods: Based on the German Pharmacoepidemiological Research Database (GePaRD), 250 cases were randomly selected (50% males) for each outcome between 2016 and 2017 based on the inclusion criteria age ≥ 50 years and continuous insurance ≥ 1 year and applying the following algorithms: hospitalization with a main diagnosis of AMI (ICD-10-GM codes I21.- and I22.-) or stroke (I63, I61, I64) or death with a hospitalization in the 60 days before with a main diagnosis of CV disease. Patient profiles were built including (i) age and sex, (ii) hospitalizations incl. diagnoses, procedures, discharge reasons, (iii) outpatient diagnoses incl. diagnostic certainty, physician specialty, (iv) outpatient encounters, and (v) outpatient dispensings. Using adjudication criteria based on clinical guidelines and risk factors, two trained physicians independently classified cases as "certain", "probable", "unlikely" or "not assessable". Positive predictive values (PPVs) were calculated as percentage of confirmed cases among all assessable cases. Results: For AMI, the overall PPV was 97.6% [95% confidence interval 94.8– 99.1]. The PPV for any stroke was 94.8% [91.3– 97.2] and higher for ischemic (98.3% [95.0– 99.6]) than for hemorrhagic stroke (86.5% [76.5– 93.3]). The PPV for CV death was 79.9% [74.4– 84.4]. It increased to 91.7% [87.2– 95.0] after excluding 32 cases with data insufficient for a decision. Conclusion: Algorithms based on hospital diagnoses can identify AMI, stroke, and CV death from German claims data with high PPV. This was the first study to show that German claims data contain information suitable for outcome validation. [ABSTRACT FROM AUTHOR]

Purpose: Anaphylaxis (ANA) is an important adverse drug reaction. We examined positive predictive values (PPV) and other test characteristics of ICD‐10‐GM code algorithms for detecting ANA as used in a multinational safety study (PASS). Methods: We performed a cross‐sectional study on routine data from a German academic hospital (2004–2019, age ≥ 18). Chart review was used for case verification. Potential cases were identified from the hospital administration system. The main outcome required at least one of the following: any type of specific in‐hospital code (T78.2, T88.6, and T80.5) OR specific outpatient code in combination with a symptom code OR in‐hospital non‐specific code (T78.4, T88.7, and Y57.9) in combination with two symptom codes. PPV were calculated with 95% confidence interval. Sensitivity analyses modified type of codes, unit of analysis, verification criteria and time period. The most specific algorithm used only primary codes for ANA (numbers added in brackets). Results: Four hundred and sixteen eligible cases were evaluated, and 78 (37) potential ANA cases were identified. PPV were 62.8% (95% CI 51.1–73.5) (main) and 77.4% (58.9–90.4) (most specific). PPV from all modifications ranged from 12.9% to 80.6%. The sensitivity of the main algorithm was 66.2%, specificity 91.5%, and negative predictive value 92.6%. Corresponding figures for the most specific algorithm were 32.4%, 98.0%, and 87.0%. Conclusions: The PPV of the main algorithm seems of acceptable validity for use in comparative safety research but will underestimate absolute risks by about a third. Restriction to primary discharge codes markedly improves PPV to the expense of reducing sensitivity. [ABSTRACT FROM AUTHOR]

Aims: To assess persistence and adherence to non-vitamin K antagonist oral anticoagulant (NOAC) treatment in patients with atrial fibrillation (AF) in five Western European healthcare settings.Methods and Results: We conducted a multi-country observational cohort study, including 559 445 AF patients initiating NOAC therapy from Stockholm (Sweden), Denmark, Scotland, Norway, and Germany between 2011 and 2018. Patients were followed from their first prescription until they switched to a vitamin K antagonist, emigrated, died, or the end of follow-up. We measured persistence and adherence over time and defined adequate adherence as medication possession rate ≥90% among persistent patients only.Results: Overall, persistence declined to 82% after 1 year and to 63% after 5 years. When including restarters of NOAC treatment, 85% of the patients were treated with NOACs after 5 years. The proportion of patients with adequate adherence remained above 80% throughout follow-up. Persistence and adherence were similar between countries and was higher in patients starting treatment in later years. Both first year persistence and adherence were lower with dabigatran (persistence: 77%, adherence: 65%) compared with apixaban (86% and 75%) and rivaroxaban (83% and 75%) and were statistically lower after adjusting for patient characteristics. Adherence and persistence with dabigatran remained lower throughout follow-up.Conclusion: Persistence and adherence were high among NOAC users in five Western European healthcare settings and increased in later years. Dabigatran use was associated with slightly lower persistence and adherence compared with apixaban and rivaroxaban. [ABSTRACT FROM AUTHOR]

Purpose This post‐authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non‐dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.8 per 10 000 first treatments. Methods: Cohort study of IV iron new users, captured mostly through pharmacy ambulatory dispensing, from populations covered by health and administrative data sources in five European countries from 1999 to 2017. Anaphylaxis events were identified through an algorithm that used parenteral penicillin as a positive control. Results: A total of 304 210 patients with a first IV iron treatment (6367 iron dextran), among whom 13–16 anaphylaxis cases were identified and reported as a range to comply with data protection regulations. The pooled unadjusted incidence proportion (IP) ranged from 0.4 (95% confidence interval [CI], 0.2–0.9) to 0.5 (95% CI, 0.3–1.0) per 10 000 first treatments. No events were identified at first dextran treatments. There were 231 294 first penicillin treatments with 30 potential cases of anaphylaxis (IP = 1.2; 95% CI, 0.8–1.7 per 10 000 treatments). Conclusion: We found an IP of anaphylaxis from 0.4 to 0.5 per 10 000 first IV iron treatments. The study captured only a fraction of IV iron treatments administered in hospitals, where most first treatments are likely to happen. Due to this limitation, the study could not exclude a differential risk of anaphylaxis between iron dextran and iron non‐dextrans. The IP of anaphylaxis in users of penicillin was consistent with incidences reported in the literature. [ABSTRACT FROM AUTHOR]

Abstract Background Human papilloma virus (HPV) types 6 and 11 account for 90 percent of anogenital warts (AGW). Assessment of a potential reduction of the incidence of AGW following introduction of HPV vaccines requires population-based incidence rates. The aim of this study was to estimate incidence rates of AGW in Germany, stratified by age, sex, and region. Additionally, the medical practitioner (gynaecologist, dermatologist, urologist etc.) who made the initial diagnosis of AGW was assessed. Methods Retrospective cohort study in a population aged 10 to 79 years in a population-based healthcare insurance database. The database included more than 14 million insurance members from all over Germany during the years 2004-2006. A case of AGW was considered incident if a disease-free period of twelve months preceded the diagnosis. To assess regional variation, analyses were performed by federal state. Results The estimated incidence rate was 169.5/100,000 person-years for the German population aged 10 to 79 years. Most cases occurred in the 15 to 40 years age group. The incidence rate was higher and showed a peak at younger ages in females than in males. The highest incidence rates for both sexes were observed in the city-states Berlin, Hamburg and Bremen. In females, initial diagnosis of AGW was most frequently made by a gynaecologist (71.7%), whereas in males, AGW were most frequently diagnosed by a dermatologist (44.8%) or urologist (25.1%). Conclusions Incidence of AGW in Germany is comparable with findings for other countries. As expected, most cases occurred in the younger age groups. The frequency of diagnoses of AGW differs between sexes and women and men receive treatment by doctors of different specialties.

Aims: Prevalence of the use of antipsychotics (APs) in the paediatric population is globally increasing. The aim of this study was to describe multinational trends and patterns in AP use in children and adolescents in Europe. Methods: This was a dynamic retrospective cohort study comprising all children and adolescents (⩽18 years of age). Data were extracted from five population-based electronic healthcare databases in Europe (Denmark, Germany, Italy, the Netherlands and United Kingdom) from 2000 to 2010. Yearly prevalence and incidence of AP use was expressed per 1000 person-years (PYs). Results: Prevalence increased from 1.44 to 3.41/1000 PYs (2008) in Denmark and from 2.07 to 4.35/1000 PYs in the NL (2009), moderately increased from 2.8 to 3.24/1000 in UK (2009) and from 1.53 to 1.74/1000 PYs in Germany (2008) and remained low from 0.61 to 0.34/1000 PYs in Italy (2010). Similarly, incidence rates increased from 0.69 to 1.52/1000 PYs in Denmark and from 0.86 to 1.49/1000 PYs in the NL, stabilised from 2.29 to 2.37/1000 PYs in the UK and from 0.79 to 0.80/1000 PYs in Germany and remained low from 0.32 to 0.2/1000 PYs in Italy. AP use was highest in 15–18 year olds and in boys compared to girls. Yet, the use observed in the 5–9 year olds was found to be comparatively high in the NL. Prescriptions of second generation APs, especially risperidone, were privileged but the first generation APs were still prescribed in the youngest. Conclusions: A steady increase in AP use in children and adolescents was observed essentially in the NL and Denmark. The use in Germany and Italy was lowest among countries. The use of APs under 9 years of age underlines their off-label use and should be carefully monitored as the risk/benefit ratio of these medications remains unclear in young children. AP use was altogether lower in Europe as compared to that reported in North America. [ABSTRACT FROM AUTHOR]