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

Study Design and Cohort Comparability in a Study of Major Cardiovascular Events in New Users of Prucalopride Versus Polyethylene Glycol 3350

INTRODUCTION: Given prior safety experience with other 5-HT4 agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride. OBJECTIVES: Our objective is to describe the methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride initiators and polyethylene glycol 3350 (PEG) initiators following a harmonized protocol. METHODS: Prucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Study exposures, cardiovascular risk factors, and other covariates were identified from healthcare utilization codes harmonized across databases. Cardiovascular outcomes were identified using database-specific algorithms based on diagnosis codes. The propensity score (PS) in each database was estimated using logistic regression, with prucalopride versus PEG as the outcome and including clinically relevant variables associated with major adverse cardiovascular events. RESULTS: In total, 12,030 prucalopride initiators and 59,985 PEG initiators were identified. After matching and trimming, cohorts from the UK and Sweden were well-balanced for cardiovascular risk factors and cancer. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators. The prevalence of these characteristics also differed from those in the UK and Sweden. The pooled analyses included only data from the UK and Sweden. CONCLUSIONS: Matching, trimming, and PS stratification yielded comparable cohorts in four of five data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany

Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation:A Multinational Population-Based Cohort Study

INTRODUCTION: The serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA. METHODS: This observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding. RESULTS: The pooled analyses included 5715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90–10.39) for patients initiating prucalopride and 10.24 (6.97–14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36–1.14). Results remained consistent in various sensitivity analyses. CONCLUSIONS: The pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG

Incidence of anogenital warts in Germany: a population-based cohort study

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

From Inception to ConcePTION: Genesis of a Network to Support Better Monitoring and Communication of Medication Safety During Pregnancy and Breastfeeding

In 2019, the Innovative Medicines Initiative (IMI) funded the ConcePTION project—Building an ecosystem for better monitoring and communicating safety of medicines use in pregnancy and breastfeeding: validated and regulatory endorsed workflows for fast, optimised evidence generation—with the vision that there is a societal obligation to rapidly reduce uncertainty about the safety of medication use in pregnancy and breastfeeding. The present paper introduces the set of concepts used to describe the European data sources involved in the ConcePTION project and illustrates the ConcePTION Common Data Model (CDM), which serves as the keystone of the federated ConcePTION network. Based on data availability and content analysis of 21 European data sources, the ConcePTION CDM has been structured with six tables designed to capture data from routine healthcare, three tables for data from public health surveillance activities, three curated tables for derived data on population (e.g., observation time and mother-child linkage), plus four metadata tables. By its first anniversary, the ConcePTION CDM has enabled 13 data sources to run common scripts to contribute to major European projects, demonstrating its capacity to facilitate effective and transparent deployment of distributed analytics, and its potential to address questions about utilization, effectiveness, and safety of medicines in special populations, including during pregnancy and breastfeeding, and, more broadly, in the general population

Imaging Strategies for Determining Diagnosis and Assessing Resectability in Patients with Suspected Pancreatic Cancer: Comparison and Clinical Decision Analysis

Titelblatt und Inhaltsverzeichnis Einleitung und Fragestellung Methodik Ergebnisse Diskussion Zusammenfassung LiteraturverzeichnisMit ca. 10.000 Todesfällen ist das Pankreaskarzinom in Deutschland die vierthäufigste krebsbedingte Todesursache. Da es gibt keine verlässlichen klinischen Zeichen oder Laborparameter zur Diagnose gibt, erfolgt die Diagnostik mittels bildgebender Verfahren, wobei die retroperitoneale Lage des Pankreas die Erkennung erschwert. Bei der Vielzahl der in den letzten Jahren entwickelten bzw. verfeinerten diagnostischen Verfahren stellt sich die Frage, welche Modalität am besten geeignet ist. Im Rahmen dieser Arbeit wurde deswegen untersucht, welches Verfahren bzw. welche Kombination von Verfahren im Hinblick auf die diagnostische Leistung bzw. das Kosten-Nutzen-Verhältnis bei der Diagnose und der Beurteilung der Resektabilität des Pankreaskarzinoms die besten Ergebnisse liefert. Die Datengrundlage lieferte eine prospektive multimodale diagnostische Studie, die zwischen 08/1999 und 11/2001 an der Charité unter der Leitung von Prof. Rosewicz, Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie (CVK), durchgeführt wurde. Als erstes wurde die diagnostische Einzelleistung dieser Verfahren bei der Diagnose und der Beurteilung der Resektabilität bei Patienten mit Verdacht auf Pankreaskarzinom verglichen: ERCP und MRT zeigten mit 95% bzw. 91% die höchste Sensitivität bezogen auf das Erkennen eines Karzinoms. Die Sensitivität bezogen auf das Erkennen eines resektablen Tumors war für MRT und EUS größer als 90% und lag für CT und US bei 83% bzw. 84%. Anschließend wurde untersucht, ob durch Kombination zweier Verfahren die diagnostische Treffsicherheit erhöht werden kann und falls ja, welche Kombinationen die besten Ergebnisse liefern. Bei der empfohlenen Kombination der Tests mit den höchsten Sensitivitäten (ERCP und MRT) steigt die Spezifität auf 91%, auf Kosten einer nur leicht reduzierten Sensitivität von 72%. Um unter Berücksichtigung verschiedener Kombinationsregeln und der entstehenden Kosten die beste Strategie zur Diagnose des Pankreaskarzinoms zu ermitteln, wurde abschließend ein Entscheidungsbaum konstruiert. Dort zeigte sich, dass alle sechs Strategien mit MRT als erster Modalität unter den besten acht waren. Die beste diagnostische Leistung erbrachte die Strategie "MRT gefolgt von ERCP für positive Ergebnisse", die 78% der Patienten richtig in benigne, maligne/resektabel und maligne/irresektabel klassifizierte. Wenn die Kosten der einzelnen diagnostischen Verfahren berücksichtigt werden, ergibt sich ein ähnliches Bild. Die Strategie "nur US" ist mit erwarteten Kosten von 37,90 Euro pro Patient mit Abstand am billigsten. Bei der Strategie "nur CT" liegen die erwarteten Kosten um 185,40 Euro höher, dafür werden ca. 10% mehr Patienten richtig diagnostiziert. Bei der Strategie "nur MRT" liegen die erwarteten Kosten um weitere 154,70 Euro höher als bei der Strategie "nur CT", bei 4% mehr richtig diagnostizierten Patienten. Wenn positive Ergebnisse des MRT mit ERCP verifiziert werden erhöhen sich die Kosten deutlich um 587,10 Euro bei einem nur marginalen diagnostischen Erkenntnisgewinn. Bis neuere Untersuchungen bzw. Erkenntnisse vorliegen, wird aufgrund dieser Arbeit empfohlen, bei Patienten mit Verdacht auf Pankreaskarzinom MRT als ersten diagnostischer Test durchzuführen. Ein positiver Befund kann anschließend, abhängig von Patientencharakteristika und klinischen Erwägungen, mittels ERCP verifiziert werden.Approximately 10,000 patients are diagnosed with pancreatic cancer (PC) each year in Germany where it is the fourth leading cause of cancer-related death. As there are no reliable clinical or laboratory markers for early diagnosis, imaging technologies have an important role in the detection and staging of PC. The multitude of available diagnostic procedures raises the question which method is best fort he diagnosis of PC. Therefore, in this thesis was examined which procedure or combination of procedures is the best regarding diagnostic power and best cost-effectiveness ratio in the detection and staging of PC. The data came from a prospective diagnostic study performed at the Charité University Hospital, Division of Hepatology and Gastroenterology, from 08/1999-11/2000. First, the single diagnostic value of the procedures for the detection and staging in patients with suspected PC was compared. ERCP and MRI had with 95% and 91% the highest sensitivity regarding the detection of a carcinoma. The sensitivity regarding the detection of a resectable tumor was for MRI and EUs bigger than 90% and was for CT and US 83% and 84%: Second, it was examines whether the combination of procedures improves diagnostic performance and if so which combination is best. The recommended combination of the two methods with the highest sensitivity (ERCP and MRI) the specificity increases to 91%, at the cost of a slightly reduced sensitivity of 72%. Finally, to determine the best strategy for the diagnosis of PC under consideration of different combination rules and accruing costs, a decision tree was built. In this analysis all six strategies with MRI as first procedure were among the best eight. The best test performance was achieved with the strategy MR followed by ERCP for positive results which classified 78% of patients correctly as benign, malignant/resectable, and malignant/unresectable. If costs are taken into account, results are similar. The strategy only US is the cheapest with expected costs of 37.90 Euro per patient. The cost of the strategy only CT are 185.40 Euro higher with about 10% more correctly classified patients. The costs of the strategy only MRI are additional 154,70 Euro higher, with 4% more correctly classified patients. If positive findings with MRI are verified with ERCP, the costs raise considerably additional 587,10 EURO with only little diagnostic improvement. Until results of further studies are available, it is recommended to use in patients with suspected PC MRI as first diagnostic procedure. A positive result may, according to patient characteristics and clinical considerations be verified by ERCP

Non-Steroidal Anti-Inflammatory Drug Use and the Risk of Acute Myocardial Infarction in the General German Population: A Nested Case–Control Study

INTRODUCTION: Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased relative risk of acute myocardial infarction (AMI), but the label warnings refer particularly to patients with cardiovascular risk factors. The magnitude of relative AMI risk for patients with and without cardiovascular risk factors varies between studies depending on the drugs and doses studied. OBJECTIVES: The aim of our study was to estimate population-based relative AMI risks for individual and widely used NSAIDs, for a cumulative amount of NSAID use, and for patients with and without a prior history of cardiovascular risk factors. METHODS: Based on data from the German Pharmacoepidemiological Research Database (GePaRD) of about 17 million insurance members from four statutory health insurance providers, for the years 2004–2009, a nested case–control study was conducted within a cohort of 3,476,931 new NSAID users classified into current, recent, or past users. Up to 100 controls were matched to each case by age, sex, and length of follow-up using risk set sampling. Multivariable conditional logistic regression was applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Duration of NSAID use was calculated by the cumulative amount of dispensed defined daily doses (DDDs), and stratified analyses were conducted for potential effect modifiers. RESULTS: Overall, 17,236 AMI cases were matched to 1,714,006 controls. Elevated relative AMI risks were seen for current users of fixed combinations of diclofenac with misoprostol (OR 1.76, 95% CI 1.26–2.45), indometacin (1.69, 1.22–2.35), ibuprofen (1.54, 1.43–1.65), etoricoxib (1.52, 1.24–1.87), and diclofenac (1.43, 1.34–1.52) compared with past use. A low cumulative NSAID amount was associated with a higher relative AMI risk for ibuprofen, diclofenac, and indometacin. The relative risk associated with current use of diclofenac, fixed combinations of diclofenac with misoprostol, etoricoxib, and ibuprofen was highest in the younger age group (&lt;60 years) and similar for patients with or without major cardiovascular risk factors. CONCLUSION: Relative AMI risk estimates differed among the 15 investigated individual NSAIDs. Diclofenac and ibuprofen, the most frequently used NSAIDs, were associated with a 40–50% increased relative risk of AMI, even for low cumulative NSAID amounts. The relative AMI risk in patients with and without cardiovascular risk factors was similarly elevated

Second dose of measles-mumps-rubella-varicella vaccine (MMRV) and the risk of febrile convulsions

INTRODUCTION: Studies have shown an increased risk of febrile convulsions (FC) after first immunization with the quadrivalent measles-mumps-rubella-varicella vaccine (MMRV) compared to a first dose of measles-mumps-rubella vaccine (MMR) only or in combination with separately administered varicella vaccine (MMR + V). Therefore, it is recommended to give MMR + V at first dose and MMRV or MMR + V at second dose. Little is known on the risk of FC after MMRV at second dose, especially whether the risk depends on age, sex, history of FC or type of first dose vaccine. METHODS: A retrospective cohort study using claims data from the German Pharmacoepidemiological Research database (GePaRD) was performed in children born between January 1st, 2004 and October 31st, 2015 who received two doses of MMRV, MMR + V or MMR. Cases were defined as hospitalization with a diagnosis of FC without neurological conditions coded as main discharge diagnosis. Unadjusted and adjusted odds ratios (OR) with 95% confidence intevals (CIs) were calculated to compare the risk of FC. Stratified analyses were performed to examine potential effect modification by age, sex, history of FC or type of first dose vaccine. RESULTS: In the first 30 days after second dose vaccination, 464 FCs were observed in a cohort of 528,639 children with a median age of 17 months. After adjustment for potential confounders, the adjusted OR for FC in the 30 days after vaccination was 1.25 (95% CI 0.67–2.30) for MMRV compared to MMR + V and 1.04 (0.82–1.32) for MMRV compared to MMR. History of FC was the most important risk factor with an OR of 36.26 (29.30–44.89). We found no effect modification by age, sex, history of FC, or type of first dose vaccine. CONCLUSION: Use of MMRV at second dose is not associated with an increased risk of FC compared to MMR + V or MMR, irrespective of age, sex, history of FC, or type of first dose vaccine

Medicaid and Medicare

Medicaid is the largest health care program for persons with low income in the US and is jointly funded by the federal and individual state governments, while Medicare is solely funded by the federal government and provides health care for the vast majority of elderly persons. Both programs were established in 1965 and are overseen by the Centers of Medicare and Medicaid Services (CMS) of the United States Department of Health and Human Services