Patient-focused outcomes after initiation of dialysis for ESRD: mortality, hospitalization and functional impairment.

BACKGROUND: Outcome data regarding clinically relevant endpoints after starting dialysis for end-stage renal disease (ESRD) are sparse, and early events after starting dialysis are particularly underestimated. The aim of this study was to describe patient-focused outcomes in ESRD patients starting from first dialysis. METHODS: The data basis for this retrospective observational study were anonymized healthcare data from Germany's largest statutory health insurer. We identified ESRD patients who initiated dialysis in 2017. Deaths, hospitalizations and occurrence of functional impairment within 4 years after starting dialysis were recorded starting from first treatment. Hazard ratios in dialysis patients compared with an age- and sex-matched reference population without dialysis were generated, stratified by age. RESULTS: The dialysis cohort included 10 328 ESRD patients who started dialysis in 2017. First dialysis was performed in-hospital for 7324 patients (70.9%), and 865 of these died during the same hospitalization. One-year mortality for ESRD patients initiating dialysis was 33.8%. Functional impairment occurred in 27.1% of patients, while 82.8% of patients required hospitalization within 1 year. Hazard ratios of dialysis patients compared with the reference population for mortality, functional impairment and hospitalization at 1-year were 8.6, 4.3 and 6.2. Dialysis patients <50 years were disproportionately affected, with >40-fold increased risk of adverse events compared with their peers. CONCLUSIONS: The emergence of morbidity and mortality after starting dialysis for ESRD is significant, especially in younger patients. Patients have a right to be informed about the prognosis associated with their condition.

[Utilizing Routine Health Insurance Data for Calculation of Disease Frequencies in the Project BURDEN 2020]. / Nutzung von Krankenkassenroutinedaten zur Bestimmung von Krankheitshäufigkeiten im Projekt BURDEN 2020.

OBJECTIVE: The concept of disease burden enables a comprehensive analysis of the health status of a population. Key indicators are years of life lost due to mortality (YLL) and morbidity (years lived with disability, YLD), summarised in the DALY indicator (disability adjusted life years). These indicators are suitable for planning prevention, health care or provision of health services. With the project BURDEN 2020, funded by the German Federal Joint Committee's Innovation Fund, a national and regionalised calculation of burden of disease for Germany is being carried out for the first time, based on the methodology of the international "Global Burden of Disease" study. METHODS: Calculation of YLD requires data on the frequency and severity of diseases, with routine health insurance data constituting an important data source. Case definitions for 18 selected diseases and severity levels for 11 of these diseases were developed in expert meetings. Based on these case definitions, the AOK Research Institute (WIdO) calculated disease frequencies from health utilisation data of patients insured with the AOK. A specific concept for prevalence calculation takes into account the dynamics of an open cohort of insurees. For severity levels, the results of the AOK insurees were extrapolated to the total population in Germany according to age and gender groups. For disease frequencies, the results were additionally adjusted for morbidity and estimated on regional levels. RESULTS: Disease frequencies measured by prevalences or rates are available for 18 diseases from seven categories (cardiovascular diseases, diabetes, cancer, mental disorders, dementia, COPD and lower respiratory tract infections) at the regional levels of the 16 federal states and 96 regional planning areas. Severity distributions are provided on the national level stratified by age groups and gender. The results and documentation of methods are available at www.krankheitslage-deutschland.de (in German language). CONCLUSION: Routine health insurance data are an important data source in the BURDEN 2020 project because regional figures and, in some cases, severity levels can be determined on the basis of a large number of cases. A comprehensive publication of results creates transparency and allows reutilisation of methods in further projects. Future research should extend burden of disease calculations to other diseases. In addition, there is an increasing demand for health data linkage.

The Burden of Disease in Germany at the National and Regional Level.

BACKGROUND: .Summary measures such as disability-adjusted life years (DALY) are becoming increasingly important for the standardized assessment of the burden of disease due to death and disability. The BURDEN 2020 pilot project was designed as an independent burden-of-disease study for Germany, which was based on nationwide data, but which also yielded regional estimates. METHODS: DALY is defined as the sum of years of life lost due to death (YLL) and years lived with disability (YLD). YLL is the difference between the age at death due to disease and the remaining life expectancy at this age, while YLD quantifies the number of years individuals have spent with health impairments. Data are derived mainly from causes of death statistics, population health surveys, and claims data from health insurers. RESULTS: In 2017, there were approximately 12 million DALY in Germany, or 14 584 DALY per 100 000 inhabitants. Conditions which caused the greatest number of DALY were coronary heart disease (2321 DALY), low back pain (1735 DALY), and lung cancer (1197 DALY). Headache and dementia accounted for a greater disease burden in women than in men, while lung cancer and alcohol use disorders accounted for a greater disease burden in men than in women. Pain disorders and alcohol use disorders were the leading causes of DALY among young adults of both sexes. The disease burden rose with age for some diseases, including cardiovascular diseases, dementia, and diabetes mellitus. For some diseases and conditions, the disease burden varied by geographical region. CONCLUSION: The results indicate a need for age- and sex-specific prevention and for differing interventions according to geographic region. Burden of disease studies yield comprehensive population health surveillance data and are a useful aid to decision-making in health policy.

N-Nitrosodimethylamine-Contaminated Valsartan and the Risk of Cancer­A Longitudinal Cohort Study Based on German Health Insurance Data.

BACKGROUND: N-Nitrosodimethylamine (NDMA), classified as a probable human carcinogen, has been found as a contaminant in the antihypertensive drug valsartan. Potentially carcinogenic effects associated with the consumption of NDMAcontaminated valsartan have not yet been analyzed in large-scale cohort studies. We therefore carried out the study reported here to explore the association between NDMA-contaminated valsartan and the risk of cancer. METHODS: This cohort study was based on longitudinal routine data obtained from a large German statutory health insurance provider serving approximately 25 million insurees. The cohort comprised patients who had filled a prescription for valsartan in the period 2012-2017. The endpoint was an incident diagnosis of cancer. Hazard ratios (HR) for cancer in general and for certain specific types of cancer were calculated by means of Cox regression models with time-dependent variables and adjustment for potential confounders. RESULTS: A total of 780 871 persons who had filled a prescription for valsartan between 2012 and 2017 were included in the study. There was no association between exposure to NDMA-contaminated valsartan and the overall risk of cancer. A statistically significant association was found, however, between exposure to NDMA-contaminated valsartan and hepatic cancer (adjusted HR 1.16; 95% confidence interval [1.03; 1.31]). CONCLUSION: These findings suggest that the consumption of NDMA-contaminated valsartan is associated with a slightly increased risk of hepatic cancer; no association was found with the risk of cancer overall. Close observation of the potential long-term effects of NDMA-contaminated valsartan seems advisable.

Effect of Sodium Bicarbonate in Kidney Transplant Recipients With Chronic Metabolic Acidosis.

BACKGROUND: Metabolic acidosis (MA) is a common complication after kidney transplantation and regarded to increase mortality, graft failure, and bone fractures. Here, we conducted a retrospective cohort study to analyze the effect of sodium bicarbonate on those events. METHODS: All kidney transplant recipients of the German health insurance Allgemeine Ortskrankenkasse (AOK) were selected, who received their transplantation between 2007 and 2015. Three groups were formed: (1) control group (no acidosis, n = 3602), (2) acidosis group (encoded acidosis, n = 370), and (3) treatment group (encoded therapy, n = 769). The study endpoints were mortality, death-censored graft failure, and bone fractures. RESULTS: The prevalence of MA in the first year after transplantation was 46.2%. The 5-year patient and graft survival were 89.8% and 89.3% in the control group, 90% and 90.8% in the acidosis group, and 87.5% and 81.6% in the treatment group, respectively. The rate of bone fractures did not differ between the groups. Neither log-rank tests nor multivariable Cox regression analyses could detect a negative impact of MA on mortality (hazard ratio [HR] 0.94; confidence interval [CI] 0.67-1.30), graft failure (HR1.18; CI 0.82-1.72), or the incidence of bone fractures (HR1.19; CI 0.92-1.55). Treatment with sodium bicarbonate was associated with an increased risk of graft failure (HR1.52; CI 1.03-2.25), whereas mortality (HR0.86; CI 0.59-1.26) and the incidence of bone fractures (HR1.16; CI 0.86-1.56) were not altered. CONCLUSIONS: MA is common after kidney transplantation but not associated with an increased frequency of death, graft failure, or bone fractures. Conversely, sodium bicarbonate therapy increased the incidence of graft failure.

Erratum to: BURDEN 2020-Burden of disease in Germany at the national and regional level.

Erratum to:Bundesgesundheitsbl (2018) https://doi.org/10.1007/s00103-018-2793-0 The original publication of this article contained an error in the list of the authors, in which the contributing author Christian Schmidt was missing. The full list of authors has now been updated. The original article ….

BURDEN 2020-Burden of disease in Germany at the national and regional level.

BACKGROUND: Evidence-based policy measures need non-interest-guided information about the health status of a population and the diseases that affect the population the most. In such cases, a national burden of disease study can provide reliable insights at the regional level. AIM: This article presents the potential of the BURDEN 2020 project and its expected outcome for Germany at the national and regional level. METHODS: The BURDEN 2020 project uses several indicators including years of life lost (YLL) to cover the impact of mortality and years lived with disability (YLD) to cover morbidity. The sum of both is the measure of population health called disability adjusted life years (DALY). RESULTS: The study ranks individual diseases and risk factors based on their impact on population health. The burden of disease approach is assumed to be sensitive to subnational differences and may generate immediate benefits for regional planning. The BURDEN 2020 study will pilot a national burden of disease study for Germany that will later be transformed into a continuous data processing and visualization tool. This is done by using, modifying and supplementing the methodology employed by the Global Burden of Disease (GBD) study to better fit the needs of health policy in Germany. This study is aimed at calculating the disease burden for up to 17 preselected diseases. Furthermore, the estimates of burden of disease are attributed to a selected set of risk factors. CONCLUSION: The Burden 2020 study will provide the results of a new, health-related data processing system to the public. This includes a noninterest-guided presentation of the burden of disease (DALY) in Germany at the national and regional level.

Antibiotic Use in Children - A Cross-National Analysis of 6 Countries.

OBJECTIVES: To describe the rates of pediatric antibiotic use across 6 countries on 3 continents. STUDY DESIGN: Cross-national analysis of 7 pediatric cohorts in 6 countries (Germany, Italy, South Korea, Norway, Spain, and the US) was performed for 2008-2012. Antibiotic dispensings were identified and grouped into subclasses. We calculated the rates of antimicrobial prescriptions per person-year specific to each age group, comparing the rates across different countries. RESULTS: A total of 74 744 302 person-years from all participating centers were included in this analysis. Infants in South Korea had the highest rate of antimicrobial consumption, with 3.41 prescribed courses per child-year during the first 2 years of life. This compares with 1.6 in Lazio, Italy; 1.4 in Pedianet, Italy; 1.5 in Spain; 1.1 in the US; 1.0 in Germany; and 0.5 courses per child-year in Norway. Of antimicrobial prescriptions written in Norway, 64.8% were for first-line penicillins, compared with 38.2% in Germany, 31.8% in the US, 27.7% in Spain, 25.1% in the Italian Pedianet population, 9.8% in South Korea, and 8% in the Italian Lazio population. CONCLUSIONS: We found substantial differences of up to 7.5-fold in pediatric antimicrobial use across several industrialized countries from Europe, Asia, and North America. These data reinforce the need to develop strategies to decrease the unnecessary use of antimicrobial agents.

Adherence to Disease Modifying Drugs among Patients with Multiple Sclerosis in Germany: A Retrospective Cohort Study.

BACKGROUND: Long-term therapies such as disease modifying therapy for Multiple Sclerosis (MS) demand high levels of medication adherence in order to reach acceptable outcomes. The objective of this study was to describe adherence to four disease modifying drugs (DMDs) among statutorily insured patients within two years following treatment initiation. These drugs were interferon beta-1a i.m. (Avonex), interferon beta-1a s.c. (Rebif), interferon beta-1b s.c. (Betaferon) and glatiramer acetate s.c. (Copaxone). METHODS: This retrospective cohort study used pharmacy claims data from the data warehouse of the German Institute for Drug Use Evaluation (DAPI) from 2001 through 2009. New or renewed DMD prescriptions in the years 2002 to 2006 were identified and adherence was estimated during 730 days of follow-up by analyzing the medication possession ratio (MPR) as proxy for compliance and persistence defined as number of days from initiation of DMD therapy until discontinuation or interruption. FINDINGS: A total of 52,516 medication profiles or therapy cycles (11,891 Avonex, 14,060 Betaferon, 12,353 Copaxone and 14,212 Rebif) from 50,057 patients were included into the analysis. Among the 4 cohorts, no clinically relevant differences were found in available covariates. The Medication Possession Ratio (MPR) measured overall compliance, which was 39.9% with a threshold MPR≥0.8. There were small differences in the proportion of therapy cycles during which a patient was compliant for the following medications: Avonex (42.8%), Betaferon (40.6%), Rebif (39.2%), and Copaxone (37%). Overall persistence was 32.3% at the end of the 24 months observation period, i.e. during only one third of all included therapy cycles patients did not discontinue or interrupt DMD therapy. There were also small differences in the proportion of therapy cycles during which a patient was persistent as follows: Avonex (34.2%), Betaferon (33.4%), Rebif (31.7%) and Copaxone (29.8%). CONCLUSIONS: Two years after initiating MS-modifying therapy, only 30-40% of patients were adherent to DMDs.

Dosage strength is associated with medication persistence with Ginkgo biloba drug products: a cohort study of ambulatory drug claims data in Germany.

BACKGROUND: Ginkgo biloba drugs (Gb) are reimbursed within the German statutory health insurance (SHI) scheme for treatment of dementia. In 2008, a novel Gb product containing 240 mg Ginkgo extract EGb761® per tablet was introduced aiming to facilitate medication use by incorporating the recommended daily dose in one single tablet. The aim of this study was to evaluate the relationship between dosage strength and persistence in a representative population of patients treated with Gb. METHODS: Retrospective cohort study in ambulatory drug claims database within the German SHI system. Persistence was defined as continuous treatment with an allowable gap of 20% between refills. Multivariate regression models were conducted to identify variables associated with persistence. RESULTS: Among 13,810 patients initiating treatment with Gb in 2008, 430 (3.1%) received a dosage strength of 240 mg, 7,070 (51.2%) a dosage strength of 120 mg and 6,310 (45.7%) dosage strengths containing less than 120 mg Gb per tablet. After 6 months, persistence was highest for patients treated with the 240 mg dosage form (22.8% of patients), although persistence was low in general (5.7% and 0% of patients treated with 120 mg and less than 120 mg, respectively). Risk for non-persistence was reduced in patients receiving 240 mg products compared to 120 mg (HR = 0.63; 95%CI 0.57 - 0.70). CONCLUSIONS: Patients initially treated with Gb 240 mg were more persistent compared to those receiving lower dosage strengths. Nevertheless, persistence with Gb therapy is generally low and should be improved in order to better realize therapeutic effects.

Adherence to antihypertensives: feasibility of two self-report instruments to investigate medication-taking behaviour in German community pharmacies.

OBJECTIVE: To design and test the feasibility of two questionnaires in German community pharmacies exploring self-reported adherence to antihypertensives. METHODS: Two self-report questionnaires were designed for patients treated with antihypertensives. The 29-item-questionnaire (long form, LF) was completed by pharmacists interviewing patients who were on the premises filling a prescription. The short form (SF; 19 items) was sent by pharmacies to patients via mail. The acceptance of the instruments by patients and pharmacists as well as the feasibility to measure medication-taking behaviour was investigated. Adherence was investigated by using a modified 5-(LF) or 6-item (SF) Morisky score. RESULTS: Of 44 community pharmacies contacted, 18 agreed to participate. Patients' response rates were 428/915 (46.8%) for the SF and 249/760 (32.8%) for the LF. One hundred and seventy-nine patients (41.8%) and 70 patients (28.1%) reported adherence problems according to the SF and LF respectively. CONCLUSIONS: To our knowledge, this is the first attempt to develop a self-report instrument for the detection of non-adherence in patients taking antihypertensives in this setting in Germany. Patients were willing to provide detailed information about their medication-taking behaviour. Underestimation of non-adherence may be more pronounced when applying the questionnaire in the pharmacy.

Incidence of thyroid hormone therapy in patients treated with sunitinib or sorafenib: a cohort study.

BACKGROUND: Sunitinib and sorafenib can induce serious adverse drug reactions (ADR) such as hypothyroidism. However, the incidence has not been reliably determined in clinical trials. AIMS: To determine incidence rates (IR) and hazard ratios (HR) of thyroid hormone (TH) therapy as a surrogate for sunitinib- and sorafenib-induced clinical hypothyroidism. METHODS: A cohort study was performed using claims data for prescriptions covering >80% of German pharmacies. Patients with a first prescription of sunitinib or sorafenib in the period between June 2006 and December 2007 were followed until incident prescription of any TH (event of interest) or censoring (due to loss to follow-up, discontinuation or switch of therapy, prescription of antithyroid drugs or the end of the study). RESULTS: One-hundred and seventy eight of 1295 sunitinib patients (13.7%) versus 77 of 1214 sorafenib patients (6.3%) received a TH. IR were 24.2 and 12.1 per 100 person-years, respectively. Unadjusted HR for TH therapy was 2.0 (95%confidence interval (CI) 1.5-2.6) for sunitinib compared to sorafenib and remained significant after adjustment for covariates, i.e. type of prescriber, region, insurance status, type of insurance fund, and relevant co-medication. CONCLUSIONS: Sunitinib- and sorafenib-induced hypothyroidism is a more frequent ADR than currently labelled. Furthermore, patients treated with sunitinib have a two-fold increased risk of requiring TH therapy compared to sorafenib. Patients being treated with sunitinib or sorafenib are, therefore, at risk of thyroid function disturbances and routine monitoring both at baseline and throughout treatment with sunitinib and sorafenib is justified.

Treatment duration (persistence) of basal insulin supported oral therapy (BOT) in Type-2 diabetic patients: comparison of insulin glargine with NPH insulin.

OBJECTIVE: To compare the persistence (treatment duration) of basal insulin supported oral therapy (BOT) using insulin glargine (GLA) or NPH insulin (NPH) in Type-2 diabetic patients. METHODS: This retrospective cohort study reports results from an analysis of claims data from prescriptions for ambulatory patients within the German Statutory Health Insurance scheme. The study is based on claims data from more than 80% of German community pharmacies. Treatment duration until switching to a basal bolus treatment regimen (intensified conventional insulin therapy: ICT) was determined in insulin-naïve patients who began treatment with BOT using GLA or NPH between 01/2003 and 12/2006. RESULTS: A total of 97,998 patients (61,070 GLA and 36,928 NPH) were included. Within the observation period, 23.5% of GLA patients and 28.0% of NPH patients switched from BOT to ICT. The upper quartile of probability of continuation of therapy (the 75th percentile) was reached after 769 days in GLA patients and after 517 days in NPH patients. Therefore, the risk of switching to ICT was significantly higher with NPH compared to GLA: hazard ratios were 1.34 (99% CI: 1.29-1.38; unadjusted) and 1.22 (99% CI: 1.18-1.27) after adjustment for predefined covariates. Various sensitivity analyses using modified inclusion criteria and endpoint definitions were applied and these confirmed the initial results. CONCLUSION: Type-2 diabetic patients under BOT with GLA stayed significantly longer on the initial therapy before switching to ICT than patients on BOT using NPH.

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice.

The Cu-binding beta-amyloid precursor protein (APP), and the amyloid Abeta peptide have been proposed to play a role in physiological metal regulation. There is accumulating evidence of an unbalanced Cu homeostasis with a causative or diagnostic link to Alzheimer's disease. Whereas elevated Cu levels are observed in APP knockout mice, APP overexpression results in reduced Cu in transgenic mouse brain. Moreover, Cu induces a decrease in Abeta levels in APP-transfected cells in vitro. To investigate the influence of bioavailable Cu, transgenic APP23 mice received an oral treatment with Cu-supplemented sucrose-sweetened drinking water (1). Chronic APP overexpression per se reduced superoxide dismutase 1 activity in transgenic mouse brain, which could be restored to normal levels after Cu treatment (2). A significant increase of brain Cu indicated its bioavailability on Cu treatment in APP23 mice, whereas Cu levels remained unaffected in littermate controls (3). Cu treatment lowered endogenous CNS Abeta before a detectable reduction of amyloid plaques. Thus, APP23 mice reveal APP-induced alterations linked to Cu homeostasis, which can be reversed by addition of dietary Cu.

Mitochondrial dysfunction, apoptotic cell death, and Alzheimer's disease.

Being major sources of reactive oxygen species (ROS), mitochondrial structures are exposed to high concentrations of ROS and might therefore be particularly susceptible to oxidative injury. Mitochondrial damage may play a pivotal role in the cell death decision. Bolstered evidence indicates that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress occurring in Alzheimer's disease (AD) finally contributing to synaptic failure and neuronal degeneration. Accumulation and oligomerization of amyloid beta (Abeta) is also thought to play a central role in the pathogenesis of this disease by probably directly leading to mitochondrial dysfunction. Moreover, numerous lines of findings indicate increased susceptibility to apoptotic cell death and increased oxidative damage as common features in neurons from sporadic AD patients but also from familial AD (FAD) cases. Here we provide a summary of recent work demonstrating some key abnormalities that may initiate and promote pathological events in AD. Finally, we emphasize a hypothetical sequence of the pathogenic steps linking sporadic AD, FAD, and Abeta production with mitochondrial dysfunction, caspase pathway, and neuronal loss.

Increased apoptotic cell death in sporadic and genetic Alzheimer's disease.

Mounting evidence indicates increased susceptibility to cell death and increased oxidative damage as common features in neurons from sporadic Alzheimer's disease (AD) patients but also from familial AD (FAD) cases. Autosomal dominant forms of FAD are caused by mutations of the amyloid precursor protein (APP) gene and by mutations of the genes encoding for presenilin 1 or presenilin 2 (PS1/2). We investigated the effect of the Swedish APP double mutation (APPsw) on oxidative stress-induced cell death mechanisms in PC12 cells. This mutation results in from three- to sixfold increased beta-amyloid (Abeta) production compared with wild-type APP (APPwt). Because APPsw cells secrete low Abeta levels similar to the situation in FAD brains, our cell model represents a very suitable approach to elucidate the AD-specific cell death pathways under more likely physiological conditions. We found that APPsw-bearing cells show decreased mitochondrial membrane potential after exposure to hydrogen peroxide. In addition, activity of the executor caspase 3 after treatment with hydrogen peroxide was elevated in APPsw cells, which seems to be the result of an enhanced activation of both intrinsic and extrinsic apoptosis pathways. Our findings provide evidence that the massive neurodegeneration in early age of FAD patients could be a consequence of an increased vulnerability of neurons by mitochondrial abnormalities resulting in activation of different apoptotic pathways as a consequence to elevated oxidative stress levels. Finally, we propose a hypothetical sequence of the pathogenic steps linking sporadic AD, FAD, Abeta production, mitochondrial dysfunction with caspase pathway, and neuronal loss.