In atrial fibrillation epilepsy risk differs between oral anticoagulants: active comparator, nested case-control study.

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.

Investigating drug safety in pregnancy based on the German Pharmacoepidemiological Research Database (GePaRD): A proof-of-concept analysis on the association between valproate and spina bifida.

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.

Use of combined oral contraceptives and risk of venous thromboembolism in young women: a nested case-control analysis using German claims data.

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.

Persistence and adherence to non-vitamin K antagonist oral anticoagulant treatment in patients with atrial fibrillation across five Western European countries.

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.

Validity of hospital ICD-10-GM codes to identify anaphylaxis.

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.

Use of intravenous iron and risk of anaphylaxis: A multinational observational post-authorisation safety study in Europe.

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.

Validity of hospital ICD-10-GM codes to identify acute liver injury in Germany.

PURPOSE: Acute liver injury (ALI) is an important adverse drug reaction. We estimated the positive predictive values (PPVs) of ICD-10-GM codes of ALI used in an international postauthorisation safety study (PASS). METHODS: Analyses used routine data (2007 to 2016, adults) from a German academic hospital in a cross-sectional design. Two algorithms from the PASS were applied to extract potential cases from the hospital information system: specific end point (A) (discharge diagnosis of liver disease-specific codes) and less specific end point (B) (discharge and outpatient-specific and nonspecific codes suggestive of liver injury). ALI cases were confirmed on the basis of plasma liver enzyme activity elevation. Secondary analysis was performed following exclusion of cases with known cancer, chronic liver, biliary and pancreatic disease, heart failure, and alcohol-related disorders, as applied in the PASS. RESULTS: On the basis of ICD codes: outcome A, 154 cases (143 with case notes and lab data for case verification); outcome B, 485 cases (357 with case notes and lab data). ALI was confirmed in 71 outcome A cases, PPV of 49.7% (95% confidence interval [CI], 41.2%-58.1%), and 100 outcome B cases, PPV of 28.0% (95% CI, 23.4%-33.0%). Applying exclusion criteria increased PPV (95% CI) to 62.7% (50.0%-74.2%) for outcome A and 45.7% (37.2%-54.3%) for outcome B. CONCLUSIONS: In safety studies on hepatotoxicity based on routine data using ICD-10-GM discharge codes and when validation of potential cases is not feasible, only the more specific codes should be used to describe ALI, and competing diagnoses for liver injury should be excluded to avoid substantial misclassification.

Optimizing an algorithm for the identification and classification of pregnancy outcomes in German claims data.

PURPOSE: For studying drug utilization and safety in pregnancy based on administrative health care data, the reliable identification and classification of pregnancy outcomes in the data is essential. We aimed to optimize an existing algorithm for the identification and classification of pregnancy outcomes in the German Pharmacoepidemiological Research Database (GePaRD) with a particular focus on births. METHODS: We reconsidered all codes used by the original algorithm and applied it to data of GePaRD from 2006 to 2014. Longitudinal records of pregnancies were used to identify targets for enhancing the algorithm's specificity. We checked the plausibility of the results, eg, regarding the age distribution of persons with pregnancy outcomes. Based on 20 longitudinal records of pregnancies, we compared the outcome classification by clinical experts with the results of the modified algorithm. RESULTS: Our algorithm identified 1 235 261 pregnancy outcomes in the database, with the majority (94%) being live births, classified as preterm (10%), term (78%), and (12%) births after the expected delivery date. The median age of pregnant women was 32 years (Q1 28; Q3 35). Implausible sequence of outcomes (for example, an induced abortion within a pregnancy categorized as ending in a live birth) were rare (0.03%). The case profile review by clinical experts resulted in the same outcome type and date as the algorithm in 95%. CONCLUSIONS: Our algorithm led to plausible results regarding the identification and classification of pregnancy outcomes. It will be an important foundation for studies on drug utilization and drug safety during pregnancy based on GePaRD.

[Prescribing valproate to girls and women of childbearing age in Germany : Analysis of trends based on claims data]. / Valproatverordnungen bei Mädchen und Frauen im gebärfähigen Alter in Deutschland : Untersuchung zeitlicher Trends basierend auf Versichertendaten.

BACKGROUND: Measures to raise awareness of the teratogenic potential of valproate and restrict its use in girls/women of childbearing age have been intensified. For Germany, the impact of these measures on valproate prescription rates remains unknown. OBJECTIVES: Trends in prescribing valproate, the underlying treatment indication, and the specialty of the prescribing physician are analyzed. MATERIALS AND METHODS: With claims data from several statutory health insurance providers from 2004 to 2016 (approximately 3.5 million insured persons per year) considering treatment indication and medical specialties of prescribing physicians, we assessed the rate of girls/women (12 to 50 years) with at least one valproate dispensation per year. RESULTS: The age-standardized rate of girls/women with at least one valproate dispensation declined by 28% between 2004 and 2016 (2.91/1000 vs. 2.09/1000). For 2015, the indications were epilepsy (66.9%), bipolar disorder (13.6%), migraine/headache (5.6%), schizoaffective disorder (4.3%), and other mental disorders (8.9%). Among epilepsy patients, the proportion treated with valproate declined from 26.2 to 16.8%, but changed little in patients with bipolar disorder (9.3% vs. 8.0%). A total of 46.3% of valproate dispensations were issued by neurologists or psychiatrists and 29.6% by general practitioners, internal medicine specialists, or family doctors. CONCLUSIONS: Based on German claims data, a decline of valproate dispensations was shown for epilepsy patients of childbearing age, while the proportion in other indications has hardly changed since 2004.

Use of azithromycin and risk of ventricular arrhythmia.

BACKGROUND: There are conflicting findings from observational studies of the arrhythrogenic potential of azithromycin. Our aim was to quantify the association between azithromycin use and the risk of ventricular arrhythmia. METHODS: We conducted a nested case-control study within a cohort of new antibiotic users identified from a network of 7 population-based health care databases in Denmark, Germany, Italy, the Netherlands and the United Kingdom for the period 1997-2010. Up to 100 controls per case were selected and matched by age, sex and database. Recency of antibiotic use and type of drug (azithromycin was the exposure of interest) at the index date (occurrence of ventricular arrhythmia) were identified. We estimated the odds of ventricular arrhythmia associated with current azithromycin use relative to current amoxicillin use or nonuse of antibiotics (≥ 365 d without antibiotic exposure) using conditional logistic regression, adjusting for confounders. RESULTS: We identified 14 040 688 new antibiotic users who met the inclusion criteria. Ventricular arrhythmia developed in 12 874, of whom 30 were current azithromycin users. The mean age of the cases and controls was 63 years, and two-thirds were male. In the pooled data analyses across databases, azithromycin use was associated with an increased risk of ventricular arrhythmia relative to nonuse of antibiotics (adjusted odds ratio [OR] 1.97, 95% confidence interval [CI] 1.35-2.86). This increased risk disappeared when current amoxicillin use was the comparator (adjusted OR 0.90, 95% CI 0.48-1.71). Database-specific estimates and meta-analysis confirmed results from the pooled data analysis. INTERPRETATION: Current azithromycin use was associated with an increased risk of ventricular arrhythmia when compared with nonuse of antibiotics, but not when compared with current amoxicillin use. The decreased risk with an active comparator suggests significant confounding by indication.

The impact of the lookback period and definition of confirmatory events on the identification of incident cancer cases in administrative data.

BACKGROUND: This cohort study examined the impact of the lengths of lookback and confirmation periods as well as the definition of confirmatory events on the number of incident cancer cases identified and age-standardized cumulative incidences (ACI) estimated in administrative data using German cancer registry data as a benchmark. METHODS: ACI per 100,000 insured persons for breast, prostate and colorectal cancer were estimated using BARMER Statutory Health Insurance claims data. Incident cancer cases were defined as having an in- or outpatient diagnosis in 2013, no diagnosis in a lookback period of 1 year and a second diagnosis (or death) in a confirmation period of 1 quarter. We varied lookback periods from 1 to 7 years, confirmation periods from 1 to 4 quarters as well as the definition of confirmatory events and compared ACI estimates to cancer registry data. RESULTS: ACI were higher for breast (138.7) and prostate (103.6) but lower for colorectal cancer (42.1) when compared to cancer registries (119.3, 98.0 and 45.5, respectively). Extending the lookback period to 7 years reduced ACI to 129.0, 95.1 and 38.3. An extended confirmation period of 4 quarters increased ACI to 151.3, 114.9 and 46.8. Including breast and colorectal surgeries as a confirmatory event reduced ACI to 114.9 and 37.1, respectively. CONCLUSIONS: The choice of lookback and confirmation periods and the definition of confirmatory events have considerable impact on the number of incident cancer cases identified and ACI estimated. Researchers need to be aware of potential misclassification when identifying incident cancer cases in administrative data. Further validation studies as well as studies using administrative data to estimate cancer incidences should consider several choices of the lookback and confirmation periods and the definition of confirmatory events to show how these parameters impact the validity and robustness of their results.

Characteristics and drug use patterns of older antidepressant initiators in Germany.

PURPOSE: The purpose of this study was to investigate characteristics, drug use patterns, and predictors for treatment choice in older German patients initiating antidepressant (AD) treatment. METHODS: Using the German Pharmacoepidemiological Research Database, we identified a cohort of AD initiators aged at least 65 years between 2005 and 2011. Potential indications, co-morbidity, and co-medication as well as treatment patterns such as the duration of the first treatment episode were assessed. In addition, a logistic regression model was used to identify independent predictors for initiating treatment with tricyclic ADs (TCAs) compared to selective serotonin reuptake inhibitors (SSRIs). RESULTS: Overall, 508,810 individuals were included in the cohort. About 55 % of patients initiated AD treatment with TCAs, followed by 22 % receiving SSRIs. During the study period, a decrease of treatment initiation with TCAs was observed. Higher age and male sex as well as being diagnosed with depression were highly associated with SSRI treatment, whereas pain and sleeping disorders were strong predictors for initiating TCA treatment. The duration of the first treatment episode was substantially longer in SSRI users compared to TCA initiators (median 119 vs. 43 days). CONCLUSIONS: Potential indications and drug use patterns in older German AD initiators varied substantially for different drug classes and single agents. Given the anticholinergic and sedative properties of TCAs, the frequent use of this drug class though probably related to indications such as pain was remarkable.

Combining evidence from multiple electronic health care databases: performances of one-stage and two-stage meta-analysis in matched case-control studies.

PURPOSE: Clustering of patients in databases is usually ignored in one-stage meta-analysis of multi-database studies using matched case-control data. The aim of this study was to compare bias and efficiency of such a one-stage meta-analysis with a two-stage meta-analysis. METHODS: First, we compared the approaches by generating matched case-control data under 5 simulated scenarios, built by varying: (1) the exposure-outcome association; (2) its variability among databases; (3) the confounding strength of one covariate on this association; (4) its variability; and (5) the (heterogeneous) confounding strength of two covariates. Second, we made the same comparison using empirical data from the ARITMO project, a multiple database study investigating the risk of ventricular arrhythmia following the use of medications with arrhythmogenic potential. In our study, we specifically investigated the effect of current use of promethazine. RESULTS: Bias increased for one-stage meta-analysis with increasing (1) between-database variance of exposure effect and (2) heterogeneous confounding generated by two covariates. The efficiency of one-stage meta-analysis was slightly lower than that of two-stage meta-analysis for the majority of investigated scenarios. Based on ARITMO data, there were no evident differences between one-stage (OR = 1.50, CI = [1.08; 2.08]) and two-stage (OR = 1.55, CI = [1.12; 2.16]) approaches. CONCLUSIONS: When the effect of interest is heterogeneous, a one-stage meta-analysis ignoring clustering gives biased estimates. Two-stage meta-analysis generates estimates at least as accurate and precise as one-stage meta-analysis. However, in a study using small databases and rare exposures and/or outcomes, a correct one-stage meta-analysis becomes essential.

Risk of venous thromboembolism in cancer patients treated with epoetins or blood transfusions.

AIMS: Anaemia is common in cancer patients, with treatments including epoetins and blood transfusions. Although an increased risk of venous thromboembolism (VTE) has been associated with both therapeutics, studies comparing the risk of VTE between epoetins and transfusions in cancer patients are lacking. METHODS: A nested case-control study investigated this risk using the German Pharmacoepidemiological Research Database. Cohort members were incident cancer patients receiving first time treatment with epoetin or transfusion. A subcohort including only patients receiving chemotherapy was created, since the formally approved indication of epoetins is chemotherapy-induced anaemia. Cases were defined as patients developing VTE. For each case up to 10 gender- and age-matched controls were selected from the cohort. Multiple confounder adjusted odds ratios (aORs) with 95% confidence intervals (CIs) for VTE and recent treatment with epoetins or transfusions (last 28 days before index date) compared with past anti-anaemic treatment were calculated by conditional logistic regression. RESULTS: Among 69 888 patients receiving first time treatment with epoetin or transfusion, 3316 VTE cases were identified. The aOR for VTE was 1.31 (95% CI 1.03, 1.65) for epoetins, 2.33 (95% CI 2.03, 2.66) for transfusions, and 2.24 (95% CI 1.34, 3.77) for epoetins and transfusions. Sensitivity analyses with a stricter VTE definition or an expanded time window yielded similar results. In the chemotherapy only subcohort the risk difference between epoetins and transfusions could not be verified (aOR 1.48, 95% CI 1.10, 1.98 vs. aOR 1.80, 95% CI 1.49, 2.19). Our study confirmed known VTE risk factors including previous VTE (aOR 14.76, 95% CI 12.79, 17.03) or surgery (aOR 1.83, 95% CI 1.67, 2.01). Epoetin-associated risk decreased after a safety warning by the European Medicines Agency setting maximum haemoglobin target values to 12 g dl(-1) . CONCLUSIONS: Transfusions could be associated with a higher VTE risk than epoetins in cancer patients. Moreover, current prescribing patterns may have decreased the VTE risk for epoetins.

Prescribing pattern of antipsychotic drugs during the years 1996-2010: a population-based database study in Europe with a focus on torsadogenic drugs.

INTRODUCTION: Antipsychotic drugs (APDs) are used to treat several mental illnesses. Some APDs have long been known to be associated with QT prolongation, potentially leading to torsades de pointes (TdP) and sudden cardiac death (SCD). In 2005, thioridazine was withdrawn because of the risk of SCD, bringing further attention to the arrhythmogenic potential of APDs. AIM: The aim of the current study was to evaluate the use of APDs in five European countries during the years 1996-2010. METHODS: A cohort study was conducted using prescription/dispensing data from seven healthcare databases [the AARHUS University Hospital Database (Denmark), the German Pharmacoepidemiological Research Database (GePaRD) (Germany), Health Search Database/Thales (HSD) and Emilia Romagna Regional Database (ERD) (Italy), PHARMO Database Network and Integrated Primary Care Information (IPCI) (the Netherlands) and The Health Improvement Network (THIN) (the UK), covering a population of 27 million individuals. The annual prescription rate of APDs was measured overall and for individual medications. APDs were classified as torsadogenic according to the Arizona-CERT list. All analyses were stratified by age, gender and calendar year. RESULTS: A total of 559 276 person-years (PYs) of exposure to APDs was captured. The crude annual prescription rate of APD use ranged from 3.0/1000 PYs in ERD to 7.7/1000 PYs in AARHUS. Among APDs with established torsadogenic potential, thioridazine was the most frequently used medication in the UK. Haloperidol was commonly prescribed in Italy and the Netherlands. The use of APDs with torsadogenic potential was much higher in elderly patients. CONCLUSIONS: Substantial use of APDs with torsadogenic potential has been reported in Europe in recent years, in spite of increasing concerns about their arrhythmogenic potential. This use was even greater in elderly patients, who are at higher risk of SCD.

Antibiotic use varies substantially among adults: a cross-national study from five European Countries in the ARITMO project.

PURPOSE: To examine patterns of outpatient and community antibiotic use among adults in five European countries. METHODS: We used healthcare data of 28.8 million adults from six population-based ARITMO project databases to ascertain information on systemic antibiotic use in Denmark (2000-2008), the Netherlands (1999-2010), Italy (2000-2010), the UK (1996-2009), and Germany (2004-2008). We estimated overall, and age-group and sex specific antibiotic use as defined daily doses (DDD) per 1000 inhabitants per day. We computed annual age- and sex-standardized population prevalence of antibiotic use per 1000 persons-years (p-y) and the mean duration (in days) of antibiotic use. RESULTS: The overall antibiotic use varied from 8.7 DDD per 1000 inhabitants per day in the UK to 18.1 DDD in Denmark, representing a 2.1-fold geographical variation. In all countries, prescribing was relatively high among individuals aged 15-19 years; lower in those aged 20-50 years; and then increased steadily reaching 41.8 DDD per 1000 inhabitants per day in individuals ≥ 85 years in Denmark. After age- and sex-standardization, prevalence of antibiotic use varied threefold from 160.2/1000 p-y in the UK to 421.1/1000 p-y in Italy. The ratio of broad- to narrow-spectrum penicillin, cephalosporin, and macrolide use varied from 0.6 in Denmark to 120.2 in Italy. Women used more antibiotics than men did in all countries. Across countries, the mean duration of antibiotic use varied 1.3 to 21.1-fold for different antibiotics. CONCLUSIONS: Antibiotic use is high in women and the elderly. Prescribing patterns vary substantially across European countries, both according to overall consumption, user prevalence, duration, and narrow- versus broad-spectrum antibiotics.

Trends in paediatric macrolide use in five European countries-a population-based study.

PURPOSE: The study aims to analyse overall as well as subgroup-specific outpatient paediatric macrolide use in five European countries, including time trends of macrolide prescription rates, and to provide potential targets for future interventions aiming to promote judicious macrolide use. METHODS: Macrolide prescription rates per 1000 person years to paediatric outpatients (≤18 years) were calculated using healthcare databases from Denmark, Germany, Italy, The Netherlands and the UK. Poisson regression analysis was used to estimate the influence of increasing calendar year on total macrolide and subgroup-specific prescription rates based on monthly data, adjusted for seasonal variations. Time periods for which data were available varied between 4 (Italy 2007-10, Germany 2005-8) and 10 years (UK 2000-9). RESULTS: Paediatric macrolide use in 2008 varied between 199 (Italy) and 47 (Netherlands) prescriptions per 1000 person years. Prescription rates of short-acting macrolides declined significantly in all countries but the UK. The use of intermediate-acting macrolides significantly rose with increasing calendar year in Denmark (rate ratio (RR) = 1.12) and the UK (RR = 1.06), but decreased in Germany (RR = 0.84) and The Netherlands (RR = 0.97). Prescription rates of long-acting agents increased in Denmark (RR = 1.05), The Netherlands (RR = 1.05) and the UK (RR = 1.11) (all trends p < 0.05). The greatest seasonal variations of macrolide use between summer and winter months were observed in Italy and Germany. CONCLUSIONS: The observed trend toward increased prescribing of intermediate- and/or long-acting agents might further increase resistance pressure on bacterial pathogens due to their prolonged plasma half-life and broader antibacterial activity. Marked seasonality of prescription rates in the high-utilising countries, Italy and Germany, suggests frequent prescription of macrolides to treat respiratory infections which may be of viral origin.

Estimation of background incidence rates of Guillain-Barré syndrome in Germany - a retrospective cohort study with electronic healthcare data.

BACKGROUND: The Guillain-Barré syndrome (GBS) occurs after infections and as an adverse reaction to vaccines. No detailed information on incidence rates (IRs) in Germany is available. METHODS: This retrospective cohort study estimated age- and sex-specific IRs of GBS in Germany in the years 2007-2009 based on electronic healthcare data from the German Pharmacoepidemiological Research Database (GePaRD). Two case definitions were applied. GBS cases had a main discharge diagnosis of GBS. GBS_PROCEDURE cases in addition had codes for relevant diagnostic procedures. Crude and standardized IRs (SIRs) with 95% confidence intervals were stratified by year, age group, sex, region and season. IR ratios (IRRs) for each stratification factor were calculated by multivariable Poisson regression. RESULTS: Among 13,297,678 persons, 889 (693) incident GBS (GBS_PROCEDURE) cases were identified. Overall SIRs per 100,000 person years were 2.4 (2.2-2.5) for GBS and 1.8 (1.7-2.0) for GBS_PROCEDURE. (S)IRs increased with age, peaking in the age group 70-79 years (IR GBS: 5.5 (4.7-6.5)) and were higher in males than in females (e.g., IR GBS: IRR = 1.5 (1.3-1.7)) and in February-April, as compared to the rest of the year. No regional pattern was observed. CONCLUSION: (S)IRs of GBS in Germany differed by age, sex and season and were comparable to those found in other studies. RESULTS might be used as a comparator in vaccine safety monitoring.

Use of rivaroxaban in Germany: a database drug utilization study of a drug started in hospital.

PURPOSE: The purpose of this drug utilization study was to describe the use of rivaroxaban in Germany during a time period in which approval was limited to the prevention of venous thromboembolism following hip or knee replacement. Additionally, we explored the feasibility of reconstructing inpatient drug use of rivaroxaban in a database where with a few exceptions inpatient prescribing information is not available. METHODS: Source of data was one statutory health insurance providing data on about seven million insurants throughout Germany. Analyses were based on a cohort of rivaroxaban users from launch (October 2008) to December 2009 and encompassed potential indications for rivaroxaban use, treatment duration, and co-prescribing of potentially interacting drugs. Start of rivaroxaban treatment was defined by the date of surgery. RESULTS: During the study period, 425 rivaroxaban users were identified contributing 440 treatment periods. For more than 82% of these episodes labelled indications could be determined. Treatment durations exceeded recommendations in 95% of the episodes following knee replacement whereas rivaroxaban use after elective hip surgery was found to be longer than recommended in 56%. Prescribing of potentially interacting medication was rare except for non-steroidal anti-inflammatory drugs. CONCLUSIONS: Overall, no important off-label use of rivaroxaban was identified. Based on several assumptions that have to be considered in the interpretation of the results our study describes a database approach to reconstruct inpatient drug use for a drug started after a coded hospital procedure, when treatment continues after hospital discharge and no change in drug use is expected in the outpatient setting.

Incidence and relative risk of hearing disorders in professional musicians.

BACKGROUND: Hearing disorders have been associated with occupational exposure to music. Musicians may benefit from non-amplified and low-intensity music, but may also have high risks of music-induced hearing loss. AIMS: To compare the incidence of hearing loss (HL) and its subentities in professional musicians with that in the general population. METHODS: We performed a historical cohort study among insurants between 19 and 66 years who were employed subject to social insurance contributions. The study was conducted with data from three German statutory health insurance providers covering the years 2004-2008 with about 7 million insurants. Incidence rates with 95% CIs of HL and the subentities noise-induced hearing loss (NIHL), conductive HL, sensorineural HL, conductive and sensorineural HL, as well as tinnitus were estimated stratified by age, sex and federal state. A Cox regression analysis was conducted to estimate adjusted HRs and two-sided 95% CIs for HL and its subentities. RESULTS: More than 3 million insurants were eligible, of whom 2227 were identified as professional musicians (0.07%). During the 4-year observation period, 283,697 cases of HL were seen, 238 of them among professional musicians (0.08%), leading to an unadjusted incidence rate ratio of 1.27. The adjusted hazard ratio of musicians was 1.45 (95% CI 1.28 to 1.65) for HL and 3.61 (95% CI 1.81 to 7.20) for NIHL. CONCLUSIONS: Professional musicians have a high risk of contracting hearing disorders. Use of already available prevention measures should reduce the incidence of HL in professional musicians.