Risk of cardiovascular events after an exacerbation of chronic obstructive pulmonary disease: results from the EXACOS-CV cohort study using the PHARMO Data Network in the Netherlands.

BACKGROUND: People living with chronic obstructive pulmonary disease (COPD) have an increased risk of experiencing cardiovascular (CV) events, particularly after an exacerbation. Such CV burden is not yet known for incident COPD patients. We examined the risk of severe CV events in incident COPD patients in periods following either moderate and/or severe exacerbations. METHODS: Persons aged ≥ 40 years with an incident COPD diagnosis from the PHARMO Data Network were included. Exposed time periods included 1-7, 8-14, 15-30, 31-180 and 181-365 days following an exacerbation. Moderate exacerbations were defined as those managed in outpatient settings; severe exacerbations as those requiring hospitalisation. The outcome was a composite of time to first severe CV event (acute coronary syndrome, heart failure decompensation, cerebral ischaemia, or arrhythmia) or death. Hazard ratios (HR) were estimated for association between each exposed period and outcome. RESULTS: 8020 patients with newly diagnosed COPD were identified. 2234 patients (28%) had ≥ 1 exacerbation, 631 patients (8%) had a non-fatal CV event, and 461 patients (5%) died during a median follow-up of 36 months. The risk of experiencing the composite outcome was increased following a moderate/severe exacerbation as compared to time periods of stable disease [range of HR: from 15.3 (95% confidence interval 11.8-20.0) in days 1-7 to 1.3 (1.0-1.8) in days 181-365]. After a moderate exacerbation, the risk was increased over the first 180 days [HR 2.5 (1.3-4.8) in days 1-7 to 1.6 (1.3-2.1) in days 31-180]. After a severe exacerbation, the risk increased substantially and remained higher over the year following the exacerbation [HR 48.6 (36.9-64.0) in days 1-7 down to 1.6 (1.0-2.6) in days 181-365]. Increase in risk concerned all categories of severe CV events. CONCLUSIONS: Among incident COPD patients, we observed a substantial risk increase of severe CV events or all-cause death following either a moderate or severe exacerbation of COPD. Increase in risk was highest in the initial period following an exacerbation. These findings highlight the significant cardiopulmonary burden among people living with COPD even with a new diagnosis.

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.

Safety and effectiveness of acellular pertussis vaccination during pregnancy: a systematic review.

BACKGROUND: Infants < 3 months of age are at highest risk for developing severe complications after pertussis. The majority of pregnant women has low concentrations of pertussis-specific antibodies and thus newborns are insufficiently protected by maternally transferred antibodies. Acellular pertussis vaccination during pregnancy was recently implemented in various countries. Here, we assessed the evidence for safety and effectiveness of pertussis vaccination during pregnancy. METHODS: We searched Medline, Embase, and ClinicalTrials.gov from January 1st 2010 to January 10th 2019. We assessed risk of bias (ROB) using the Cochrane ROB tool and ROBINS-I. We evaluated the quality of evidence using the GRADE approach. RESULTS: We identified 1273 articles and included 22 studies (14 for safety; 8 for effectiveness), comprising 1.4 million pregnant women in safety studies and 855,546 mother-infant-pairs in effectiveness studies. No significant differences between vaccinated and unvaccinated women and their infants were observed for safety outcomes with the exception of fever and chorioamnionitis. Compared to no vaccination, three studies showed a significantly increased relative risk for the presence of the ICD-9 code for chorioamnionitis in electronic patient data after pertussis vaccination. However, no study reported an increased risk for clinical sequelae of chorioamnionitis after vaccination during pregnancy, such as preterm birth or neonatal intensive care unit admission. Vaccine effectiveness against pertussis in infants of immunized mothers ranged from 69 to 91% for pertussis prevention, from 91 to 94% for prevention of hospitalization and was 95% for prevention of death due to pertussis. Risk of bias was serious to critical for safety outcomes and moderate to serious for effectiveness outcomes. GRADE evidence quality was moderate to very low, depending on outcome. CONCLUSION: Although an increased risk for a diagnosis of fever and chorioamnionitis was detected in pregnant women after pertussis vaccination, there was no association with a higher frequency of clinically relevant sequelae. Vaccine effectiveness for prevention of infant pertussis, hospitalization and death is high. Pertussis vaccination during pregnancy has an overall positive benefit-risk ratio. In view of the overall quality of available evidence ongoing surveillance of chorioamnionitis and its potential sequelae is recommended when pertussis vaccination in pregnancy is implemented. TRIAL REGISTRATION: PROSPERO CRD42018087814, CRD42018090357.

Incidence of second primary malignancies in metastatic castration-resistant prostate cancer: results from observational studies in three countries.

Aim: This reports some of the first incidence rate (IR) estimates of second primary malignancies (SPMs) in men with metastatic castration-resistant prostate cancer (mCRPC) in three countries. Patients & methods: Claims data from the German Pharmacoepidemiological Research Database; registry data from the Prostate Cancer Data Base Sweden; and combined registry-claims data from the US Surveillance, Epidemiology and End Results-Medicare database were analyzed to obtain overall survival and incidence of SPMs in men with mCRPC. Results: SPMs occurred in 308 German (n = 2360), 273 Swedish (n = 2849) and 172 US (n = 2234) men with mCRPC. IRs of SPMs were 79.0 (95% CI: 70.4-88.4), 101.7 (95% CI: 90.3-114.5) and 59 (95% CI: 50-68) per 1000 person-years in German, Swedish and US cohorts, respectively. Conclusion: These studies report some of the first IR estimates of SPMs in men with mCRPC, providing a historical risk estimate of SPM in this patient population.

Sodium-glucose co-transporter-2 inhibitors and the risk of fractures of the upper or lower limbs in patients with type 2 diabetes: A nested case-control study.

AIMS: To investigate whether the use of SGLT-2 inhibitors is associated with an increased risk of fractures. MATERIAL AND METHODS: We conducted a cohort study with nested case-control analysis based on the InGef database between November 2011 and December 2016 among patients with type 2 diabetes who were initiating treatment with, switching to, or adding a new class of non-insulin antidiabetic drug. Patients with a hospital or ambulatory diagnosis of fractures of the upper or lower limbs were included and were matched to up to 40 randomly sampled control subjects. Conditional logistic regression was used to estimate confounder adjusted odds ratios (ORs) of fractures, comparing current use of metformin plus SGLT-2 inhibitor or metformin plus another antidiabetic drug class to metformin plus DPP-4 inhibitor as reference. RESULTS: The cohort comprised 210 042 new users of non-insulin antidiabetic drugs. For the nested case-control analysis, 7522 patients with fractures were matched to 296 845 control subjects. In the crude and confounder adjusted analyses, current use of metformin plus SGLT-2 inhibitor compared to current use of metformin plus DPP-4 inhibitor was not associated with fractures (OR: 1.00; 95% CI: 0.72-1.39 and OR: 0.99; 95% CI: 0.71-1.37, respectively). Similarly, no statistically significant association was found for current use of metformin plus another antidiabetic drug class. No treatment effect modification was observed after stratification by number of documented risk factors for falls and fractures (< 4 vs ≥ 4) and age (< 75 vs ≥ 75 years). CONCLUSION: Our study suggests that use of SGLT-2 inhibitors and other antidiabetic drug classes are not associated with an increased risk of fractures of the upper or lower limbs compared to use of DPP-4 inhibitors in patients with type 2 diabetes.

Drug-induced kidney injury: A large case series from the Berlin Case-Control Surveillance Study
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OBJECTIVES: Drug-induced kidney injury (DIKI) may affect patients regardless of their baseline kidney function. Therefore, this study evaluated DIKI in patients with or without previous chronic kidney disease (CKD). MATERIALS AND METHODS: Potential DIKI cases were ascertained using the network of the Berlin Case-Control Surveillance Study in all 51 Berlin hospitals from April 2010 until December 2011. Via face-to-face interviews and medical chart reviews, information on all previous drug intake, comorbidities, and demographics was gathered. Included were adult patients with a new diagnosis of acute kidney injury or an acute-on-chronic kidney injury, and with an at least "possible" drug etiology based on the standardized causality assessment of the World Health Organization. Excluded were patients with prerenal or postrenal etiology, bacterial interstitial nephritis, or previous renal transplantation. RESULTS: Overall, 143 patients with DIKI were included in the study (mean age 68.4 ± 15.6 years). Of those, 77 (54%) had prediagnosed CKD. The most common symptom at onset was anuria/oliguria, while 73 patients (51%) underwent renal replacement therapy, and 11 patients (8%) died. Cardiovascular drugs, such as furosemide, torasemide, hydrochlorothiazide, and ramipril (33%), systemic anti-infectives, such as vancomycin (23%), and musculoskeletal drugs, such as ibuprofen and diclofenac (15%), were most commonly causal for DIKI. Of the 37 patients with DIKI caused by nonsteroidal anti-inflammatory drugs (NSAIDs), 20 (54%) had prediagnosed CKD. CONCLUSION: Nephrotoxicity can be caused by numerous medications, highlighting the importance of increased vigilance among physicians. Moreover, NSAIDs seem to exhibit nephrotoxic properties even in patients with normal baseline kidney function.
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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.

From prescription-only (Rx) to over-the-counter (OTC) status in Germany 2006-2015: pharmacological perspectives on regulatory decisions.

PURPOSE: Little is known about the extent of switches from prescription-only (Rx) to over-the-counter (OTC) status in Europe and about the pharmacological properties of the switched substances. The objectives of this study were to provide an overview of the substances that were switched from Rx to OTC status in Germany between 2006 and 2015 and to assess their pharmacological properties. METHODS: Session minutes of the German Expert Advisory Committee for Prescription-Only Issues, changes to the German Ordinance on Prescription-Only Medicines and the Summary of Product Characteristics of the switched substances were analysed. Pharmacological properties were studied in relation to the EU Guideline on Changing the Classification for the Supply of a Medicinal Product for Human Use (the 'EU switch guide'). RESULTS: Between 2006 and 2015, seven substances (almotriptan, omeprazole, benzydamine, ibuprofen/pseudoephedrine, racecadotril, ketotifen and levonorgestrel) were switched from Rx to OTC status in Germany. In all cases, the OTC status was restricted to certain indications, doses, pack sizes, or other limitations. Notwithstanding recommendations of the EU switch guide, some of the switched substances might interact with commonly used drugs potentially resulting in serious adverse drug reactions or have contraindications or warnings regarding substantial parts of the population. CONCLUSIONS: The stipulations of the EU switch guide were fully met for only some switches, while this was not completely the case for others. Further development of guidance on balancing risks and benefits of OTC availability is recommended.

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.

Outpatient antidepressant drug use in children and adolescents in Germany between 2004 and 2011.

PURPOSE: Recent studies on the utilization of antidepressant drugs in minors are scarce, methodologically limited, and do not factor in off-label use sufficiently. Beyond that, little is known about the short treatment durations that have been observed for many young antidepressant users. The present study examined antidepressant use in pediatric patients aged 0 to 17 years over time, investigated changes regarding the prescribed drugs, analyzed underlying diagnoses, and assessed the rate of off-label use. METHODS: We used claims data of roughly two million individuals to calculate annual prevalence and incidence rates of antidepressant prescriptions for the years 2004 to 2011. Analyses were stratified by age, sex, and drug type. For antidepressant users, numbers of prescriptions, frequencies of disorders/diseases, and specialties of the prescribing physicians were examined. The share of off-label prescriptions was calculated for each year. RESULTS: The prescription prevalence of antidepressants ranged between 1.7 and 2.1 per 1000 minors. The use of tricyclic antidepressants decreased from 0.9 to 0.6 prescriptions per 1000 minors, while the use of selective serotonin reuptake inhibitors increased from 0.5 to 1.1. Of the patients with an antidepressant prescription, 46.4% only received one prescription. Depression was by far the most frequent diagnosis among all antidepressant users as well as among subjects with only one prescription. In 2011, 36.3% of all prescriptions were off-label. CONCLUSIONS: The high proportion of single prescriptions, even in patients with a diagnosed depression, and the high rate of off-label use are particularly noteworthy and should be further investigated in future studies. Copyright © 2016 John Wiley & Sons, Ltd.

Extent and risks of antidepressant off-label use in children and adolescents in Germany between 2004 and 2011.

PURPOSE: So far, only little is known about antidepressant off-label use in pediatric patients. This is the first study examining the prevalence and the risks of off-label antidepressant prescriptions in minors over time in Germany and analyzing patterns regarding age, sex, drug class, and type of off-label use. METHODS: We used claims data of about two million individuals (<18 y) to calculate the share of off-label antidepressant prescriptions for the years 2004 to 2011, stratified by age, sex, and drug class. Off-label prescriptions were analyzed regarding underlying diagnoses, the prescribing doctor's specialty, and the type of off-label use. Incidence rates of adverse events were calculated for off- and on-label use, and the risk of suicidal events associated with off- or on-label use was examined in a nested case-control study. RESULTS: The prevalence of off-label prescriptions decreased from 58.0% to 40.9%. Selective serotonin reuptake inhibitors were more frequently prescribed off-label than tricyclic antidepressants (37.7% vs 17.5% in 2011). The most common type of off-label use was off-label use by age, followed by off-label use by indication, and off-label use by contraindication. Adverse events were rare with no significant differences between on- and off-label use. CONCLUSIONS: Although off-label antidepressant use in minors decreased over time, it is still common. However, this rather indicates a lack of approved drugs for the treatment of depression in this population than inappropriate medical treatment. This is supported by the fact that off-label use was not associated with a higher risk of adverse events than on-label use.

Immobilization and high platelet count are associated with thromboembolic complications in heparin-induced thrombocytopenia.

PURPOSE: Immune-mediated heparin-induced thrombocytopenia (HIT type II, HIT) is a potentially serious adverse drug reaction characterized by an increased risk of venous and arterial thrombosis. This study aimed to identify risk factors associated with the development of these complications. METHODS: Our study cohort included patients with HIT assembled in our pharmacovigilance center by reports from 51 collaborating hospitals in Berlin, Germany. To identify risk factors for thromboembolic complications, patients with thromboembolic events (cases) were compared to those without thromboembolic events (controls) in a case-control design. We applied univariable and multivariable logistic regression analysis to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) for potential risk factors of thromboembolic complications. RESULTS: Our cohort comprised 209 HIT patients. Of those, 53 developed thromboembolic complications. Most HIT patients received heparin for medical indications (42.1%) or in the context of cardiovascular surgery (40.2%). Of the 78 thromboembolic complications, 49 (63%) and 29 (37%) were observed in the venous and arterial vascular bed, respectively. The main locations were deep vein thrombosis (39.7%), pulmonary embolism (16.7%), and limb artery thrombosis (16.7%). In multivariable analysis, immobilization prior to HIT (OR 4.6, 95% CI 1.2-18.0; P = .026) and higher platelet counts before initiation of heparin therapy (OR 1.004, 95% CI 1.000-1.008; P = .046) were independently associated with the occurrence of thromboembolic events. CONCLUSIONS: Immobilization and a high platelet count (with a low effect size) are additional risk factors of thromboembolic complications in the course of HIT.

Characterization of new users of cilostazol in the UK, Spain, Sweden, and Germany.

PURPOSE: To describe the characteristics of new users of cilostazol in Europe with the aim to support the evaluation of its benefit/risk as used in regular clinical practice before the implementation of labeling changes recommended by the European Medicines Agency. METHODS: New users of cilostazol were identified in populations enrolled in five European health automated databases in the UK (The Health Improvement Network [THIN]), Spain (EpiChron cohort and Information System for the Improvement of Research in Primary Care [SIDIAP]), Sweden (National Registers), and Germany (German Pharmacoepidemiological Research Database [GePaRD]) between 2002 and 2012. New users were characterized according to the prevalence of cardiovascular disease and other comorbidities, concurrent use of interacting medications, new contraindications, duration of use, and potential off-label prescribing. RESULTS: We identified 22 593 new users of cilostazol. The median age was between 68.0 (THIN) and 73.7 (Sweden) years. More than 78% of users had concomitant cardiovascular disease, and between 78.8% (GePaRD) and 91.6% (THIN) were treated with interacting medications. Prevalence of new cardiovascular contraindications ranged from 1.5% (THIN) to 11.6% (GePaRD), and concurrent use of two or more antiplatelet drugs ranged from 6.3% (SIDIAP) to 13.5% (EpiChron cohort). Between 39.4% (Sweden) and 52.9% (THIN) of users discontinued cilostazol in the first 3 months. Between 41.0% (SIDIAP) and 93.4% (THIN) were considered to have received cilostazol according to the European Medicines Agency labeling. CONCLUSIONS: In this collaborative European study, most cilostazol users were elderly patients with a high prevalence of cardiovascular diseases and other comorbidity and concurrent use of interacting drugs, indicating that this is a vulnerable population at high risk of complications, especially cardiovascular events. © 2017 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

Outpatient antipsychotic drug use in children and adolescents in Germany between 2004 and 2011.

Studies from different countries showed increasing use of antipsychotics in pediatric patients. However, these studies were methodologically limited and could not assess underlying diagnoses and off-label use sufficiently. This is the first study to examine antipsychotic prescriptions in a representative sample of minors over a long period, looking at changes regarding substances and drug classes, underlying diagnoses, and the rate of off-label use. Claims data of about two million pediatric subjects were used to calculate annual prevalences and incidence rates of antipsychotic prescriptions for the years 2004-2011. Analyses were stratified by sex, age, and drug type. Numbers of prescriptions, frequencies of diseases/disorders, the prescribing physicians' specialties, and the share of off-label prescriptions were examined. During the study period, the prevalence of antipsychotic prescriptions ranged between 2.0 and 2.6 per 1000 minors. Antipsychotic prescriptions in children younger than 6 years decreased from 2.42 per 1000 subjects in 2004 to 0.48 in 2011. Among antipsychotic users, 47.0 % had only one prescription and hyperkinetic disorder was, by far, the most frequent diagnosis. The annual share of off-label prescriptions varied between 61.0 and 69.5 %. Antipsychotics were mainly prescribed to manage aggressive and impulsive behaviors in hyperkinetic disorder patients. This explains the high share of off-label prescriptions but raises concerns, since efficacy and safety of antipsychotics in this indication have not been sufficiently investigated. The decreasing antipsychotic use in younger children and the high proportion of antipsychotic users with one-time prescriptions are striking and should be further investigated in the future.

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.

Validating mortality in the German Pharmacoepidemiological Research Database (GePaRD) against a mortality registry.

PURPOSE: The study aimed at validating the status and date of death of a large electronic health insurance database against data of a mortality registry, using a probabilistic record linkage. METHODS: Data were obtained from one local health insurance company contributing to the German Pharmacoepidemiological Research Database (GePaRD). Furthermore, data of the Bremen Mortality Index (BreMI) containing all information from death certificates were used as reference information. Both data sources were probabilistically linked. The study sample consisted of insurants dying in 2005 or 2006. RESULTS: Of 3245 deaths in GePaRD, 83.7% were successfully linked to BreMI records. The linkage success did not differ between men and women, age groups or insurance status groups. Date of death was accurate in 97.1% of all linked deaths. CONCLUSIONS: The accuracy of the status of death in GePaRD is likely to be underestimated in this study because of factors related to the record linkage procedure leading to failure of the probabilistic record linkage approach and the limited completeness of BreMI. A previous validation study comparing aggregate mortality information in GePaRD with German national statistics did not indicate an overreporting of deaths in GePaRD. Thus, a higher accuracy of the status of death in GePaRD than estimated here can be assumed. Copyright © 2016 John Wiley & Sons, Ltd.

Herb-Induced Liver Injury in the Berlin Case-Control Surveillance Study.

Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed.

[Optimizing ADHD Treatment? Results of a Pilotstudy of the ADHD Selective Contract in Bremerhaven, Germany]. / Auf dem Weg zu einer optimale(re)n Versorgung? Ergebnisse der Pilotierung eines ADHS-Selektivvertrages nach §+73c SGB V in Bremerhaven.

BACKGROUND: The attention deficit hyperactivity disorder (ADHD) is associated with substantial impairment and psychiatric comorbidities. Thus, an optimized treatment is essential. In 2011, a new multidisciplinary treatment strategy (so-called Versorgungsvertrag) was contracted for the model region of Bremerhaven, Germany. This manuscript describes the results of the feasibility testing, focusing on the effects of the Versorgungsvertrag on patients' ADHD symptoms and on the treatment satisfaction of patients' kins. MATERIAL AND METHODS: Patients with ADHD (4-17 years) were assessed at baseline and at 9 months follow-up. Kins documented the current symptomatology using the FBB-ADHS questionnaire on both occasions, and rated their satisfaction with the Versorgungsvertrag at follow-up. The FBB-ADHS gives information on the severity of the ADHD core symptoms (0=normal, 3=very noticeable). RESULTS: 69 patients (77 kins) were included. At follow-up, data from 59 patients (67 kins) were available. FBB-ADHS data of both occasions was available for 44 patients. Improvements regarding the ADHD total score (1.27 at follow-up vs. 1.59 at baseline, p=0.003) and the subdomains inattention (1.42 vs. 1.81, p=0.001) and hyperactivity (0.96 vs. 1.22, p=0.032) were documented. In the subgroup of boys (n=34), inattention (p=0.001), impulsivity (p=0.019) and the ADHD total score (p=0.002) improved, while no changes were observed in the subgroup of girls (n=10). The majority of kins (52.4 to 68.4%) rated the treatment as helpful. DISCUSSION: Our study shows improvements for the ADHD core symptoms after 9 months and a high satisfaction of kins with the treatment strategy. Due to the lack of a control group from routine care, no certain statement about the additional benefit of the treatment strategy can be made. The null effect in the subgroup of girls might be explained by the underrepresentation of girls, but the gender distribution observed in our study is commonly observed in patients with ADHD. CONCLUSION: The positive effects during the observation period should be confirmed in further studies including a control group from routine care.

[Percutaneous coronary interventions : Use between 2004 and 2012 in Germany]. / Perkutane koronare Interventionen : Einsatz zwischen 2004 und 2012 in Deutschland.

BACKGROUND AND OBJECTIVE: Percutaneous coronary interventions (PCIs) are increasingly being performed in the treatment of coronary artery disease. The aim of this study is to describe the frequency of PCIs by age, sex, type, and setting of the intervention in Germany. METHODS: Based on routine data of more than eight million insurants from three statutory health insurance funds, quarterly sex- and age-specific intervention rates were calculated between 2004 and 2012. Moreover, inpatient PCIs were subdivided into PCIs with conventional bare metal stents (BMS) and PCIs with drug-eluting stents (DES). Rates were age- and sex-standardized according to the age and sex distribution of the particular years in Germany. RESULTS: Standardized rates increased from 277.3 to 382.2 per 100,000 person-years between 2004 and 2012. The intervention rate was three times higher in men than in women. The relative increase in the overall rate and in the rate of PCI with DES during the study period were 38 and 548 % respectively, whereas the rate of PCI with BMS declined by 48 %. Of all PCIs, 7-11 % were outpatient PCIs during the study period. CONCLUSIONS: PCIs are increasingly being performed in Germany, particularly PCI with DES. The frequency of PCI with BMS implantation is decreasing. Sex-specific differences in the frequency of PCI go beyond differences that would have been expected because of a differing morbidity profile. Our analyses indicate that comparatively few outpatient PCIs are performed.