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

Bone marrow mesenchymal stromal cell-derived extracellular matrix displays altered glycosaminoglycan structure and impaired functionality in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematologic malignancies characterized by clonal hematopoiesis, one or more cytopenias such as anemia, neutropenia, or thrombocytopenia, abnormal cellular maturation, and a high risk of progression to acute myeloid leukemia. The bone marrow microenvironment (BMME) in general and mesenchymal stromal cells (MSCs) in particular contribute to both the initiation and progression of MDS. However, little is known about the role of MSC-derived extracellular matrix (ECM) in this context. Therefore, we performed a comparative analysis of in vitro deposited MSC-derived ECM of different MDS subtypes and healthy controls. Atomic force microscopy analyses demonstrated that MDS ECM was significantly thicker and more compliant than those from healthy MSCs. Scanning electron microscopy showed a dense meshwork of fibrillar bundles connected by numerous smaller structures that span the distance between fibers in MDS ECM. Glycosaminoglycan (GAG) structures were detectable at high abundance in MDS ECM as white, sponge-like arrays on top of the fibrillar network. Quantification by Blyscan assay confirmed these observations, with higher concentrations of sulfated GAGs in MDS ECM. Fluorescent lectin staining with wheat germ agglutinin and peanut agglutinin demonstrated increased deposition of N-acetyl-glucosamine GAGs (hyaluronan (HA) and heparan sulfate) in low risk (LR) MDS ECM. Differential expression of N-acetyl-galactosamine GAGs (chondroitin sulfate, dermatan sulfate) was observed between LR- and high risk (HR)-MDS. Moreover, increased amounts of HA in the matrix of MSCs from LR-MDS patients were found to correlate with enhanced HA synthase 1 mRNA expression in these cells. Stimulation of mononuclear cells from healthy donors with low molecular weight HA resulted in an increased expression of various pro-inflammatory cytokines suggesting a contribution of the ECM to the inflammatory BMME typical of LR-MDS. CD34+ hematopoietic stem and progenitor cells (HSPCs) displayed an impaired differentiation potential after cultivation on MDS ECM and modified morphology accompanied by decreased integrin expression which mediate cell-matrix interaction. In summary, we provide evidence for structural alterations of the MSC-derived ECM in both LR- and HR-MDS. GAGs may play an important role in this remodeling processes during the malignant transformation which leads to the observed disturbance in the support of normal hematopoiesis

Allogeneic hematopoietic stem cell transplantation in patients aged 60-79 years in Germany (1998-2018): a registry study

Incidences of diseases treated with transplantation frequently peak at higher age. The contribution of age to total risk of transplantation has not been estimated amidst an aging society. We compare outcomes of 1,547 patients aged 70-79 years and 9,422 patients aged 60-69 years transplanted 1998-2018 for myeloid, lymphoid and further neoplasia in Germany. To quantify the contribution of population mortality to survival, we derive excess mortality based on a sex-, year- and agematched German population in a multistate model that incorporates relapse and graft-versus-host-disease (GvHD). Overall survival, relapse-free survival (RFS) and GvHD-free-relapse-free survival (GRFS) is inferior in patients aged 70-79 years, compared to patients aged 60-69 years, with 36% (95% Confidence Interval [CI]: 34-39%) versus 43% (41-44%), 32% (30- 35%) versus 36% (35-37%) and 23% (21-26%) versus 27% (26-28%) three years post-transplant (P1 year relapse-free is 6.7 (median, 95% CI: 4.5-9.4, 70-79 years) versus 9 (8.4-10.1, 60-69 years) years since landmark. Three years after RFS of one year, excess NRM is 14% (95% CI: 12-18%) in patients aged 70-79 versus 12% [11-13%] in patients aged 60-69, while population NRM is 7% (6-7%) versus 3% (3-3%). Mortality for reasons other than relapse, GvHD, or age is as high as 27% (24-29%) and 22% (22-23%) four years after transplantation. In conclusion, survival amongst older patients is adequate after allogeneic stem cell transplantation

Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation

Background The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K). Methods Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal–Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate. Results Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002). Conclusion In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making

Real-world experience of CPX-351 as first-line treatment for patients with acute myeloid leukemia

Abstract To investigate the efficacy and toxicities of CPX-351 outside a clinical trial, we analyzed 188 patients (median age 65 years, range 26–80) treated for therapy-related acute myeloid leukemia (t-AML, 29%) or AML with myelodysplasia-related changes (AML-MRC, 70%). Eighty-six percent received one, 14% two induction cycles, and 10% received consolidation (representing 22% of patients with CR/CRi) with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity (<10−3) as measured by flow cytometry. After a median follow-up of 9.3 months, median overall survival (OS) was 21 months and 1-year OS rate 64%. In multivariate analysis, complex karyotype predicted lower response (p = 0.0001), while pretreatment with hypomethylating agents (p = 0.02) and adverse European LeukemiaNet 2017 genetic risk (p < 0.0001) were associated with lower OS. Allogeneic hematopoietic cell transplantation (allo-HCT) was performed in 116 patients (62%) resulting in promising outcome (median survival not reached, 1-year OS 73%), especially in MRD-negative patients (p = 0.048). With 69% of patients developing grade III/IV non-hematologic toxicity following induction and a day 30-mortality of 8% the safety profile was consistent with previous findings. These real-world data confirm CPX-351 as efficient treatment for these high-risk AML patients facilitating allo-HCT in many patients with promising outcome after transplantation

Fingolimod, teriflunomide and cladribine for the treatment of multiple sclerosis in women of childbearing age: Description of drug utilization and exposed pregnancies in Germany

BACKGROUND: Authorizations of fingolimod, teriflunomide and cladribine were accompanied by risk minimization measures concerning their teratogenic potential. Real-world data on their use are scarce. We aimed to assess trends in the use of fingolimod, teriflunomide and cladribine among women of childbearing age, estimate the number of pregnancies occurring under treatment and explore the occurrence of malformations in newborns exposed during early pregnancy in Germany. METHODS: Using the German Pharmacoepidemiological Research Database (GePaRD, claims data from ∼20% of the German population), we determined annual age-standardized prevalences of fingolimod, teriflunomide and cladribine use from their authorization until 2019 among women aged 13–49 years (cross-sectional analyses). In longitudinal analyses, we estimated the number of exposed pregnancies by assessing whether there was an overlap between the exposure windows assigned to dispensations and the onset of pregnancy or a dispensation in the first eight weeks of pregnancy. For live births, a mother-baby linkage was performed. All available data of children with in-utero exposure and malformation codes in the first year of life were reviewed to verify the occurrence of congenital malformations. RESULTS: For fingolimod, the age-standardized prevalence of use per 1,000 females increased from 0.14 in 2011 to 0.46 in 2019; for teriflunomide, from 0.06 in 2013 to 0.28 in 2019; for cladribine, from 0.01 in 2017 to 0.07 in 2019. The proportion of users aged ≤40 years was 60% for fingolimod, 45% for teriflunomide and 65% for cladribine. We identified 136 pregnancies exposed to fingolimod, 50 to teriflunomide and one to cladribine. For fingolimod and teriflunomide, respectively, 72% and 62% of exposed pregnancies ended in a live birth. Mother-newborn linkage was successful in 64 (fingolimod) and 20 (teriflunomide) live-born children. Among these, there were six with relevant malformations (mainly heart defects) for fingolimod and two for teriflunomide. CONCLUSION: Use of fingolimod, teriflunomide and cladribine among women of childbearing age has substantially increased in Germany. A high proportion of users was in age groups in which pregnancies typically occur. Despite risk minimization measures, early pregnancy exposure to these drugs was observed

Estimating incidence and case fatality of thyroid storm in Germany between 2007 and 2017: A claims data analysis

BACKGROUND: Given the paucity of epidemiological studies on thyroid storm, we aimed to estimate the incidence rate and case fatality of thyroid storm in Germany based on a large claims database. METHODS: Using the German Pharmacoepidemiological Research Database (GePaRD) we identified patients with at least one inpatient discharge diagnosis of thyroid storm (International Statistical Classification of Diseases and Related Health Problems, 10th revision, German modification; ICD-10-GM E05.5) between 2007 and 2017 and calculated age-standardized and age-specific incidence rates in males and females (no age restriction). We defined deaths occurring within 30 days of the diagnosis as thyroid storm-associated and determined case fatality by sex and age group. Point estimates were reported with confidence intervals [CIs]. RESULTS: We identified 1690 patients with an incident diagnosis of thyroid storm. Of these, 72% were females (n = 1212). The mean age was 60 years (standard deviation: 18.6 years). The age-standardized incidence rate per 100,000 persons per year was 1.4 [CI 1.2–1.7] in females and 0.7 [CI 0.5–0.9] in males. In females ≤60 and &gt;60 years of age, the incidence rate was 0.9 [CI 0.9–1.0] (males: 0.4 [CI 0.3–0.4]) and 2.7 [CI 2.5–2.9] (males: 1.7 [CI 1.5–1.9]), respectively. The case fatality of thyroid storm was 1.4% [CI 0.6–2.8] in females ≤60 years and 10.9% [CI 8.6–13.7] in females &gt;60 years. In males, the case fatality was 1.0% [CI 0.2–4.0] in those aged ≤60 years and 16.7% [CI 12.6–21.7] in those &gt;60 years. CONCLUSIONS: Incidence rates of thyroid storm were markedly higher in females than in males and were three times higher in persons &gt;60 years compared with younger age groups. The case fatality was below 2% in persons aged ≤60 years and markedly higher in older persons (males: 17 times and females: 8 times)

Use of isotretinoin among girls and women of childbearing age and occurrence of isotretinoin-exposed pregnancies in Germany: A population-based study

BACKGROUND: Exposure to isotretinoin during pregnancy must be avoided due to its teratogenicity, but real-world data on its use are scarce. We aimed to describe (i) isotretinoin use in women of childbearing age in Germany; (ii) the occurrence of isotretinoin-exposed pregnancies; and (iii) malformations among children exposed in utero. METHODS AND FINDINGS: Using observational data from the German Pharmacoepidemiological Research Database (GePaRD, claims data from approximately 20% of the German population), we conducted annual cross-sectional analyses to determine age-standardized prevalence of isotretinoin use between 2004 and 2019 among girls and women aged 13 to 49 years. In cohort analyses, we estimated the number of exposed pregnancies by assessing whether there was prescription supply overlapping the beginning of pregnancy (estimated supply was varied in sensitivity analyses) or a dispensation within the first 8 weeks of pregnancy. Data of live-born children classified as exposed in a critical period according to these criteria were reviewed to assess the presence of congenital malformations. The age-standardized prevalence of isotretinoin use per 1,000 girls and women increased from 1.20 (95% confidence interval [CI]: 1.16, 1.24) in 2004 to 1.96 (95% CI: 1.92, 2.01) in 2019. In the base case analysis, we identified 178 pregnancies exposed to isotretinoin, with the number per year doubling during the study period, and at least 45% of exposed pregnancies ended in an induced abortion. In sensitivity analyses, the number of exposed pregnancies ranged between 172 and 375. Among live-born children, 6 had major congenital malformations. The main limitation of this study was the lack of information on the prescribed dose, i.e., the supply had to be estimated based on the dispensed amount of isotretinoin. CONCLUSIONS: Isotretinoin use among girls and women of childbearing age increased in Germany between 2004 and 2019, and there was a considerable number of pregnancies likely exposed to isotretinoin in a critical period. This highlights the importance of monitoring compliance with the existing risk minimization measures for isotretinoin in Germany

Number of pregnancies exposed to isotretinoin between 2004 and 2019 in GePaRD by age group and year of beginning of pregnancy.

Number of pregnancies exposed to isotretinoin between 2004 and 2019 in GePaRD by age group and year of beginning of pregnancy.</p