Tania Schink

Introduction: In Germany, there is a lack of recent population-based data regarding the prevalence of multiple personality disorder (MPD; ICD-10: F44.81) and the treatment of individuals with this diagnosis. This study aimed to assess the prevalence, psychiatric comorbidities, and treatment of MPD in Germany.Materials and Methods: Based on nationwide claims data, an observational trend study was conducted. For each year from 2012 to 2021, the proportion of persons with at least one coded MPD diagnosis was determined, stratified by sex, age and region. Additionally, psychiatric comorbidity, psychopharmacotherapy, hospital treatment, and outpatient psychotherapy among persons diagnosed with MPD in 2021 were assessed.Results: From 2012 to 2021, the administrative prevalence of MPD increased by 58.5% (from 4.1/100,000 to 6.5/100,000), with a prevalence peak in 17- to 24-year-olds and a female/male ratio of 6:1. In 2021, 86.4% of individuals with a MPD diagnosis had at least one co-occurring psychiatric diagnosis, with 23.9% having five or more. Top comorbidities were anxiety disorders (73.7%), depressive disorders (60.5%), other personality disorders (38.9%), substance use disorders (18.4%), and eating disorders (15.4%). Regarding pharmacotherapy, antidepressants (47.4%), tranquilisers (31.5%), antipsychotics (28.0%), and opioid analgesics (12.8%) were most frequently prescribed. 44.4% of individuals with MPD received psychotherapy, and 14.2% underwent psychiatric hospitalisation (median duration: 7 weeks).Discussion: In this study, we found an administrative prevalence of MPD of 4.1/100,000 in 2012 and 6.5/100,000 in 2021. These figures are considerably lower than those found in epidemiological studies, indicating underdiagnosis of MPD in Germany. The increase in MPD diagnoses was mainly due to a surge in outpatient diagnoses. Individuals with MPD diagnoses had high psychiatric comorbidity, especially depression, anxiety, and personality disorders. Therapeutic measures were in line with current guidelines, with the exception of above-average opioid analgesics prescriptions, which may be related to the high BPD comorbidity.

Background: Although use of inhibitors of the renin–angiotensin–aldosterone system (RAAS-I) is contraindicated in the second and third trimesters of pregnancy, a relevant number of pregnancies is still exposed. Fetopathy in children exposed after gestational week (GW) 20 is well described, but data on long-term outcomes are scarce. Our study aims to describe postnatal and long-term outcomes after fetal exposure to RAAS-I. Methods: We included all pregnancies in the German Pharmacoepidemiological Research Database GePaRD (claims data; 20% of the total German population) with exposure to RAAS-I or the antihypertensives recommended during pregnancy, i.e., metoprolol or methyldopa (HYP) after GW 20. We assessed diagnoses characteristic of RAAS-I-related fetopathy in the first 180 days after birth and examined long-term outcomes of children with and without neonatal fetopathy, especially hypertension and kidney disease. Results: Overall, we identified 203 live born children exposed to RAAS-I, of whom 61 were exposed to angiotensin II receptor blockers (ARBs), and 29,674 live born children exposed to HYP. Diagnoses consistent with RAAS-I-related fetopathy were seen in eight of the RAAS-I exposed newborns (3.9%) and in seven of the 61 ARB-exposed newborns (11.5%). Median follow-up in children without fetopathy was 4.0 years in both exposure groups. Among non-fetopathy children exposed to RAAS-I, three (1.5%) were diagnosed with hypertension or received antihypertensive prescriptions, compared to 176 children (0.6%) exposed to HYP. Conclusions: Risk of fetopathy is higher after fetal exposure to ARBs than to angiotensin-converting enzyme inhibitors. In a small proportion of children, sequelae of fetal RAAS-I exposure might only manifest in the years following birth. Graphical

Background Hyperthyroidism during pregnancy is associated with maternal, obstetric and fetal complications. Antithyroid drugs (ATDs) including carbimazole (CMZ), methimazole (MMI) and propylthiouracil (PTU) are the main pharmacotherapies for hyperthyroidism. Exposure to CMZ and MMI during the first trimester was associated with birth defects, while PTU is assumed to be the safer alternative. Objective To calculate the prescription prevalences of ATDs in women of childbearing age over time and to describe pregnancies occurring after or during ATD use. Methods Using the GePaRD database (claims data; 20% of the German population), we conducted year-wise cross-sectional studies for the period 2004–2020 to calculate prescription prevalences of CMZ, MMI and PTU in females aged 13–49 years. In longitudinal analyses, we included all women with any ATD dispensing between 2005 and 2020 aged 13–49 years at the first dispensing. We identified pregnancies occurring in this cohort and described ATD use before and during pregnancy. Results The age-standardized prescription prevalence of ATDs decreased by 32.1% between 2004 (2.71 per 1000) and 2020 (1.84 per 1000). This decrease was attributable to CMZ (2004: 1.40 per 1000; 2020: 0.76 per 1000; relative decrease: 45.7%) and MMI (2004: 1.25 per 1000; 2020: 0.99 per 1000; relative decrease: 20.8%). In the cohort including 9723 women, 13,586 pregnancies were observed, of which 67% (n = 9140) occurred after ATD use. In 16.2% of the pregnancies (n = 2203), ATD use overlapped with pregnancy onset. The proportion exposed to CMZ/MMI at pregnancy onset decreased from 30.7% in 2005 to 10.9% in 2020. In 16.5% of pregnancies (n = 2243), ATD use was started during pregnancy. Conclusion The prescription prevalence of ATD overall and specifically of CMZ/MMI in girls and women of childbearing age decreased between 2005 and 2020 in Germany. The decrease in exposure to CMZ/MMI at pregnancy onset indicates that physicians became increasingly aware of the potential risks of CMZ/MMI to the unborn child.

Background: Hyperthyroidism during pregnancy is associated with maternal, obstetrical and fetal complications. Antithyroid drugs (ATD) including carbimazole (CMZ), methimazole (MMI) and propylthiouracil (PTU) are the main pharmacotherapy for hyperthyroidism. Exposure to CMZ and MMI during the first trimester was associated with birth defects, while PTU is assumed to be the safer alternative. Objective: To calculate the prescription prevalences of ATD in women of childbearing age over time and to describe pregnancies occurring after or during ATD use. Methods: Using the GePaRD database (claims data; 20% of the German population), we conducted year-wise cross-sectional studies for the period 2004-2020 to calculate prescription prevalences of CMZ, MMI and PTU in females aged 13-49 years. In longitudinal analyses, we included all women with any ATD dispensing between 2005 and 2020 aged 13- 49 years at the first dispensing. We identified pregnancies occurring in this cohort and described ATD use before and during pregnancy. Results: The age-standardized prescription prevalence of ATDs decreased by 32.1% between 2004 (2.71 per 1,000) and 2020 (1.84 per 1,000). This decrease was attributable to CMZ (2004: 1.40 per 1,000; 2020: 0.76 per 1,000; relative decrease: 45.7%) and MMI (2004: 1.25 per 1,000; 2020: 0.99 per 1,000; relative decrease: 20.8%). In the cohort including 9,723 women, 13,586 pregnancies were observed, of which 67% (n=9,140) occurred after ATD use. In 16.2% of the pregnancies (n=2,203), ATD use overlapped with pregnancy onset. The proportion exposed to CMZ/MMI at pregnancy onset decreased from 30.7% in 2005 to 10.9% in 2020. In 16.5% of pregnancies (n=2,243), ATD use was started during pregnancy. Conclusion: The prescription prevalence of ATD overall and specifically of CMZ/MMI in girls and women of childbearing age decreased between 2005 and 2020 in Germany. The decrease in exposure to CMZ/MMI at pregnancy onset indicate that physicians became increasingly aware of the potential risks of CMZ/MMI to the unborn child.

Purpose: This study evaluated the long-term safety of roflumilast in patients with chronic obstructive pulmonary disease or chronic bronchitis using electronic healthcare databases from Germany, Norway, Sweden, and the United States (US). Patients and Methods: The study population consisted of patients aged ≥ 40 years who had been exposed to roflumilast and a matched cohort unexposed to roflumilast. The matching was based on sex, age, calendar year of cohort entry date (2010– 2011, 2012, or 2013), and a propensity score that included variables such as demographics, markers of chronic obstructive pulmonary disease (COPD) severity and morbidity, and comorbidities. In comparison to the unexposed matched cohort (never use), three exposure definitions were used for the exposed matched cohort: ever use, use status (current, recent, past use), and cumulative duration of use. The main outcome was 5-year all-cause mortality. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CI). Results: 112,541 unexposed and 23,239 exposed patients across countries were included. Some variables remained unbalanced after matching, indicating higher COPD disease severity among the exposed patients. Adjusted HRs of 5-year all-cause mortality for “ever use” of roflumilast, compared to “never use”, were 1.12 (95% CI, 1.08– 1.17) in Germany, 1.00 (95% CI, 0.92– 1.08) in Norway, 0.98 (95% CI, 0.92– 1.04) in Sweden, and 1.16 (95% CI, 1.12– 1.20) in the US. Compared to never users, there was a decrease in 5-year mortality risk observed among “current users” in Germany (HR: 0.93, 95% CI: 0.88– 0.98), Norway (HR: 0.77, 95% CI: 0.67– 0.87), and Sweden (HR: 0.80, 95% CI: 0.73– 0.88). Conclusion: There was no observed increase in 5-year mortality risk with the use of roflumilast in Sweden or Norway. A small increase in 5-year mortality risk was observed in Germany and the US in the ever versus never comparison, likely due to residual confounding by indication.

Objectives To describe opportunities and challenges experienced from the four pharmacoepidemiological database studies included in the rivaroxaban post authorisation safety study (PASS) programme and propose ways to maximise the value of population-based observational research when addressing regulatory requirements. Design PASS programme of rivaroxaban carried out as part of the regulatory postapproval commitment to the European Medicines Agency. Setting Clinical practice in Germany, the Netherlands, Sweden and the UK (electronic health records)—undertaken by pharmacoepidemiology research teams using country-specific databases with different coding structures. Participants 355 152 patients prescribed rivaroxaban and 338 199 patients prescribed vitamin K antagonists. Results Two major challenges that were encountered throughout the lengthy PASS programme were related to: (1) finalising country-tailored study designs before the extent of rivaroxaban uptake was known, and (2) new research questions that arose during the programme (eg, those relating to an evolving prescribing landscape). Recommendations We advocate the following strategies to help address these major challenges (should they arise in any future PASS): conducting studies based on a common data model that enable the same analytical tools to be applied when using different databases; maintaining early, clear, continuous communication with the regulator (including discussing the potential benefit of studying drug use as a precursor to planning a safety study); consideration of adaptive designs whenever uncertainty exists and following an initial period of data collection; and setting milestones for the review of study objectives.

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). 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)]. 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. Created by BioRender.com.

The safety and effectiveness of rivaroxaban versus vitamin K antagonists (standard of care [SOC]) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) was evaluated in Europe. Observational studies were conducted in the UK, the Netherlands, Germany, and Sweden. Primary safety outcomes were hospitalization for intracranial hemorrhage, gastrointestinal bleeding, or urogenital bleeding among new users of rivaroxaban and SOC with NVAF; outcomes were analyzed using cohort (rivaroxaban or SOC use) and nested case-control designs (current vs non-use). Statistical analyses comparing rivaroxaban and SOC cohorts were not performed. Overall, 162,919 rivaroxaban users and 177,758 SOC users were identified. In the cohort analysis, incidence ranges for rivaroxaban users were 0.25–0.63 events per 100 person-years for intracranial bleeding, 0.49–1.72 for gastrointestinal bleeding, and 0.27–0.54 for urogenital bleeding. Corresponding ranges for SOC users were 0.30–0.80, 0.30–1.42, and 0.24–0.42, respectively. In the nested case-control analysis, current SOC use generally presented a greater risk of bleeding outcomes than non-use. Rivaroxaban use (vs non-use) was associated with a higher risk of gastrointestinal bleeding, but a similar risk of intracranial or urogenital bleeding, in most countries. Ischemic stroke incidence ranged from 0.31–1.52 events per 100 person-years for rivaroxaban users. Incidences of intracranial bleeding were generally lower with rivaroxaban than with SOC, whereas incidences of gastrointestinal and urogenital bleeding were generally higher. The safety profile of rivaroxaban for NVAF in routine practice is consistent with findings from randomized controlled trials and other studies.

Background Use of the direct oral anticoagulant rivaroxaban has strongly increased in Europe since its market approval for non-valvular atrial fibrillation in 2011. Patients characteristics of rivaroxaban initiators may have changed over time but this has not been investigated so far. Objective We aimed to describe time trends of patient baseline characteristics among new rivaroxaban users with non-valvular atrial fibrillation from 2011 to 2016/17 in two European countries. Methods We used data from Germany (German Pharmacoepidemiological Research Database) and the Netherlands (PHARMO Database Network). We included new rivaroxaban users with (i) a first dispensing between 2011 and 2016/17, (ii) ≥ 2 years of age, and (iii) a diagnosis of non-valvular atrial fibrillation and described their baseline medication and comorbidity prior to starting rivaroxaban stratified by year of inclusion. Results Overall, 130,652 new rivaroxaban users were included during the study period (Germany: N = 127,743, the Netherlands: N = 2909). The sex ratio and median age remained relatively stable over time. The proportion of patients without prior use of oral anticoagulants before initiation of rivaroxaban increased in both countries between 2011 and 2016/17 (Germany: from 51 to 76%, the Netherlands: from 57 to 85%). In Germany, we observed a relative decrease by 27% in the proportion of new rivaroxaban users with a history of ischemic stroke and by 18% in the proportion with a transient ischemic attack at baseline. No such a pattern was observed in the Netherlands. The proportion of patients with heart failure at baseline showed a three-fold increase in the Netherlands, while there was a relative decrease by 12% in Germany. Conclusions Patient characteristics of new rivaroxaban users with non-valvular atrial fibrillation changed between 2011 and 2016/17, but changes differed between countries. These patterns have methodological implications. They have to be considered in the interpretation of observational studies comparing effectiveness and safety of oral anticoagulants, especially regarding potential bias due to unmeasured confounding.