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Objectives Emerging treatments for relapsed or refractory multiple myeloma (rrMM) have led to increasing options for many patients. This study aimed to assess changes in utilization of these options in Germany with a focus on modern triplet regimens including new agents, such as carfilzomib, ixazomib, elotuzumab and daratumumab, and to evaluate whether this had an impact on rrMM‐related outcomes over time. Methods The study population consisted of 1255 rrMM patients who were assigned to one of the following 6 treatment groups: immunomodulatory drug (IMiD)‐based doublets, proteasome inhibitor (PI)‐based doublets, daratumumab monotherapy, PI‐IMiD‐based triplets, monoclonal antibodies (mAbs)‐based triplets, or other treatment. Results Use of triplet‐based therapy regimens increased from 5.9% in 2014 to 31.4% in 2017. In parallel, use of IMiD‐based doublets decreased from 74.3% in 2014 to 37.6% in 2017. Over the same time period, the risk of death decreased by 32% and the risk of hospitalization which was reduced by 30%. The risk for serious adverse events remained unchanged. Conclusions Between 2014 and 2017, the use of triplet‐based therapy regimens for rrMM in Germany has significantly increased and this was associated with a significant decline in deaths and hospitalizations without an increased incidence of serious adverse events.

Background This study assessed changes in anticoagulation therapy over time in patients with atrial fibrillation (AF). Methods Analyses were performed on a claims-based dataset of 4 million health-insured individuals. The study population consisted of patients newly initiating a non-vitamin-K oral anticoagulants (NOACs) or vitamin K antagonist (VKA) for AF between 2013 and 2016. The study outcomes consisted of the proportion of patients who had (1) discontinued OAC treatment, (2) switched from VKA to NOAC, (3) switched from NOAC to VKA or (4) switched from one NOAC to another. Predictors of discontinuation or switching of OAC treatment were determined by Cox proportional hazards regression models with time-independent and time-dependent covariates. Results The study population comprised 51,606 AF patients initiating VKA (n = 21,468, 41.6%), apixaban (n = 8,832, 17.1%), dabigatran (n = 3,973, 7.7%) or rivaroxaban (n = 17,333, 33.6%). After 1 year, 29.9% of VKA and 29.5% of NOAC patients had discontinued OAC treatment without switching to another anticoagulant. A total of 10.7% of VKA patients switched to NOACs within 1 year, whereas 4.9% NOAC patients had switched to VKA. Of AF patients who were initiated on a NOAC, 5.2% switched to another NOAC. Treatment changes among NOAC starters were strongly associated with occurrence of stroke, myocardial infarction and gastrointestinal bleeding after treatment initiation. For VKA starters switching to a NOAC, stroke and bleeding events were associated with an increased likelihood of switching. Conclusion Overall discontinuation rates of VKA and NOACs are comparable over the first year of therapy, while switching from VKA to NOAC was more common than from NOAC to VKA. The majority of treatment changes were associated with clinical events.

Underuse of oral anticoagulation (OAC) for stroke prevention in atrial fibrillation (AF) results in thousands of preventable strokes in Germany each year. This study aimed to assess changes in antithrombotic therapy in AF patients after increased use of direct oral anticoagulants (DOACs) in Germany and to evaluate whether the adoption of DOAC therapy was associated with changes in AF-related stroke and bleeding over time. Analyses were carried out on a large claims-based dataset of 4 million health-insured Germans. The study population consisted of 601,261 prevalent AF patients between 2011 and 2016 who were assigned to one of the following four treatment groups: DOAC, VKA, antiplatelets or no antithrombotic treatment. Treatment patterns were descriptively analysed and represented by cohort and CHA2DS2-VASc score. Clinical outcomes before and after the adoption of DOAC therapy were assessed using Poisson regression models. Use of OAC increased from 42 to 61% between 2011 and 2016, mainly due to more frequent prescription of DOACs. However, some underuse of OAC therapy remained even in high risk AF patients. In parallel with the increased prescription rate of OAC, there was an overall 24% incidence reduction in stroke between 2011 and 2016 which was mainly driven by reductions in ischemic strokes. Over the same time period the risk for major bleeding remained unchanged. Between 2011 and 2016, the use of guideline-conform antithrombotic therapy in Germany has significantly increased. This was associated with a significant decline in strokes without an increased incidence of bleeding complications.

Transplantation proceedings 52(10), 3103-3111 (2020). doi:10.1016/j.transproceed.2020.02.159, Published by Elsevier Science, Amsterdam [u.a.]

Zusammenfassung Hintergrund Venose Thromboembolien (VTE) manifestieren sich hauptsachlich in der tiefen Venenthrombose (TVT) oder der Lungenembolie (LE) und stellen weltweit die dritthaufigste kardiovaskulare Erkrankung dar. Belastbare Daten zur VTE-Inzidenz fur Deutschland liegen derzeit jedoch nicht vor. Ziel der Arbeit Schatzung und Vergleich der Inzidenz der VTE auf Basis unterschiedlicher Routinedaten des deutschen Gesundheitswesens. Methoden Zur Schatzung und zum Vergleich der Inzidenz der VTE, TVT und LE wurden zwei Datensatze, die sowohl Informationen aus dem ambulanten als auch aus dem stationaren Bereich enthalten, herangezogen: der Datentransparenzverordnungs-Datensatz (DaTraV), der Daten aller gesetzlich Versicherten enthalt, und der Datensatz des Health Risk Institutes (HRI), der Daten von ca. 70 einzelnen Krankenkassen enthalt. Zusatzlich wurde eine arztbasierte Datenbank (IMS Disease Analyzer), die Informationen aus dem ambulanten Bereich enthalt, als Datenquelle genutzt. Ergebnisse Alters- und geschlechtsspezifische Verlaufe der VTE-Krankheitslast waren zwischen allen genutzten Datenbanken vergleichbar. Im Hinblick auf die Hohe der Krankheitslast ergaben sich zwischen den Datenbanken jedoch deutliche Unterschiede. Die Analyse der DaTraV-Daten ergab eine VTE-Inzidenz von 0,14%. Ergebnisse basierend auf Daten der HRI-Daten waren vergleichbar (0,17–0,20%). Die VTE-Inzidenz auf Basis des IMS Disease Analyzers war hingegen vergleichsweise hoch (0,32%). Diskussion Ergebnisse zur VTE-Inzidenz, die auf den DaTraV-Daten und HRI-Daten basieren, lassen sich gut in den internationalen Forschungskontext einordnen, wohingegen die Analyse des IMS Disease Analyzers aufgrund der Mehrfachzahlung erkrankter Personen vermutlich zu einer Uberschatzung der VTE-Inzidenz fuhrte. Unterschiedliche Routinedaten des Gesundheitswesens konnen teilweise zu sehr heterogenen Ergebnissen fuhren. Die Wahl der adaquaten Datenquelle bei Routinedatenanalysen sollte daher in Abhangigkeit von der vorliegenden Fragestellung und der Qualitat der Datensatze erfolgen.

All pivotal trials have evaluated non–vitamin K oral antagonists (NOACs) against warfarin. However, in some regions of the world, phenprocoumon is the most widely used vitamin K antagonist (VKA). There is little evidence documenting effectiveness and safety of NOACs compared with phenprocoumon in atrial fibrillation (AF). A retrospective cohort study using a German claims database was conducted to assess effectiveness (stroke, systemic embolism [SE]) and safety (bleeding leading to hospitalization) during therapy with NOACs and phenprocoumon in 61,205 AF patients. Hazard ratios (HRs) for effectiveness and safety outcomes were derived from Cox proportional hazard models, adjusting for baseline characteristics. Propensity score matching was performed as a sensitivity analysis. As a prespecified subgroup analysis, the effects of reduced NOAC dosing were compared with phenprocoumon. A total of 61,205 patients were identified in whom phenprocoumon (n = 23,823, 38.9%), apixaban (n = 10,117, 16.5%), dabigatran (n = 5,122, 8.4%), or rivaroxaban (n = 22,143, 36.2%) was initiated. After adjusting for baseline confounders, all three NOACs tested had significantly lower risks of stroke/SE compared with phenprocoumon (apixaban—HR: 0.77, 95% CI: 0.66–0.90; dabigatran—HR: 0.74, 95% CI: 0.60–0.91; rivaroxaban—HR: 0.86, 95% CI: 0.76–0.97). Apixaban (HR: 0.58, 95% CI: 0.49–0.69) and dabigatran (HR: 0.64, 95% CI: 0.50–0.80) were associated with lower bleeding risks than phenprocoumon, whereas the risk was similar for rivaroxaban and phenprocoumon. All three NOACs showed reduced risk of intracranial bleeding compared with phenprocoumon. Reduced doses of NOACs were predominantly used in patients with advanced age and comorbidities with generally similar effectiveness and safety benefits compared with phenprocumon as standard-dose NOACs.

Background In Germany, several triplet therapies for treating relapsed or refractory multiple myeloma (rrMM) patients have recently been approved. While most of them are administered intravenously, ixazomib-based combination is the only orally bioavailable regimen. Objective To conduct a 1-year and 3-year budget impact analysis (BIA) of different novel triplets to treat patients with rrMM in second or subsequent therapy lines accounting for costs covered by German statutory health insurance (SHI). Methods A 3-state partitioned survival model (PSM) was developed to evaluate the budget impact of the following regimens: carfilzomib plus lenalidomide plus dexamethasone (KRd), elotuzumab plus lenalidomide plus dexamethasone (ERd), daratumumab plus lenalidomide plus dexamethasone (DRd), and ixazomib plus lenalidomide plus dexamethasone (IRd). The analysis included direct medical costs such as drug acquisition, comedication and preparation for parenteral solutions, drug administration and other 1-time costs, adverse event management costs and direct non-medical costs, such as transportation costs. Results Based on current drug market shares in German healthcare market, the estimated costs after 1 year of treatment was €551 million (KRd), €163 million (ERd), €584 million (DRd), and €95 million (IRd). The total budget impact of €1393 million is mainly driven by drug acquisition and subsequent therapy costs. Conclusion Among the regimens of interest, the oral-based therapy regimens offered cost advantages over intravenous-based therapy regimens. The higher overall costs of intravenous therapy regimens were attributed primarily to higher drug acquisition costs.

Patients with non-valvular atrial fibrillation (NVAF) have a five times higher stroke risk. For more than 50 years, vitamin K antagonists (VKAs) have been the primary medication for stroke prevention. Apixaban, a non-vitamin K oral anticoagulant (NOAC), has demonstrated better efficacy and safety characteristics than the VKA warfarin in the ARISTOTLE trial. This study aims to quantify the potential societal effects of using apixaban instead of VKA in the German NVAF population from 2017 to 2030.Using an existing Markov model and a dynamic population approach, we modelled the health benefits of apixaban in patients with NVAF compared to VKA therapy in the German population from 2017 to 2030.The results represent the extrapolated direct long-term health benefits of apixaban over VKA therapy for the German NVAF population. From 2017 until 2030, the use of apixaban instead of a VKA could avoid 52,185 major clinical events. This includes 15,383 non-fatal strokes or SEs, 22,483 non-fatal major bleeds, and 14,319 all-cause deaths, which correspond to 109,887 life years gained.This study demonstrated that using apixaban instead of VKA for stroke prevention can lead to considerable reduction in cardiovascular events.

Venous thromboembolism (VTE) mainly manifests as deep vein thrombosis (TVT) or pulmonary embolism (LE), and is the third most common cardiovascular disease worldwide. However, robust evidence on the incidence of VTE in Germany is lacking.Estimation and comparison of the incidence of VTE based on different routine data sources of the German healthcare system.Estimates and comparisons of the incidence of VTE, TVT and LE were made using two databases that both covered the inpatient and the outpatient setting; the DaTraV database comprising information of all persons subject to compulsory health insurance, and the Health Risk Institute (HRI) database derived from approximately 70 statutory health insurance funds. In addition, IMS Disease Analyzer, a medical record database comprising information from the outpatient setting, was used as a data source.Patterns of age- and sex-specific VTE incidence estimates were comparable between all databases used. However, estimates based on the medical record database were comparatively high. Analyses of DaTraV data led to a VTE incidence of 0.14%. Use of HRI data yielded comparable results (0.17-0.20%). VTE incidence based on data of the IMS Disease Analyzer was comparatively high (0.32%).Results on the VTE incidence based on DaTraV or HRI date are comparable to international evidence, whereas the use of the IMS Disease Analyzer data presumably led to an overestimation due to double-counting of VTE cases. Different types of routine healthcare data sources can therefore lead to very heterogeneous results. Thus, the selection of adequate data sources strongly depends on the study question and the quality of the dataset.

Non-vitamin K antagonist oral anticoagulants (NOACs) are at least as effective and safe as vitamin K antagonists (VKAs) for stroke prevention in atrial fibrillation (AF). All pivotal trials have compared NOACs to warfarin. However, other VKAs are commonly used, for instance phenprocoumon.A retrospective cohort study using a German claims database assessed the comparative risks of bleeding leading to hospitalization during therapy with NOACs and phenprocoumon in AF patients. Endpoints consisted of major bleeding, gastrointestinal bleeding, and any bleeding. Data were collected from January 1, 2013 to March 31, 2015. Patients newly initiated on dabigatran, apixaban, rivaroxaban, or phenprocoumon were included. Hazard Ratios for bleeding events were derived from Cox proportional hazard models, adjusting for differences in baseline characteristics. Propensity score matching was performed as a sensitivity analysis.A total of 35,013 patients were identified, including 3138 on dabigatran, 3633 on apixaban, 12,063 on rivaroxaban, and 16,179 on phenprocoumon. Patients prescribed apixaban or phenprocoumon were older compared to those on dabigatran or rivaroxaban and had a higher CHAApixaban therapy is associated with a significantly reduced risk of bleeding compared to phenprocoumon. Bleeding risk with dabigatran was similar to that of phenprocoumon but bleeding risk with rivaroxaban was higher.

Norepinephrine (NE) stimulates phospholipase D (PLD) activity and cell proliferation in vascular smooth muscle cells (VSMCs). The objective of this study was to determine the contribution of PKC-ζ to NE-induced PLD activation and cell proliferation in VSMCs. PLD activity was measured by the formation of [ 3 H]phosphatidylethanol in VSMCs labeled with [ 3 H]oleic acid and exposed to ethanol. A high basal PLD activity was detected, and NE increased PLD activity over basal by 70%. This increase was abolished by the broad-range PKC inhibitor Ro 31-8220 (1 μmol/L, 30 minutes) and myristoylated PKC-ζ pseudosubstrate peptide inhibitor (25 μmol/L, 1 hour). Transfection of VSMCs with PKC-ζ antisense, but not sense, oligonucleotides, which reduced PKC-ζ protein level and basal PLD activity, caused a 92% decrease in NE-induced PLD activation. NE-induced increase in PLD activity was also reduced by 61% in cells transfected with kinase-deficient FLAG-T410A-PKC-ζ plasmid but not in those transfected with wild-type PKC-ζ. NE increased immunoprecipitable PKC-ζ activity and phosphorylation, reaching a maximum at 2 and 5 minutes, respectively. NE-induced increase in PKC-ζ activity was inhibited by Ro 31-8220 and by the pseudosubstrate inhibitor. Treatment of VSMCs for 48 hours with PKC-ζ antisense, but not sense, oligonucleotides also inhibited basal and NE-stimulated cell proliferation by 54% and 57%, respectively, as measured by [ 3 H]thymidine incorporation. The inhibitor of PLD activity n -butanol, but not its inactive analog tert -butanol, also reduced the basal and blocked NE-induced cell proliferation. These data suggest that PKC-ζ mediates PLD activation and cell proliferation elicited by NE in rabbit VSMCs.