Safety profile of rivaroxaban in first-time users treated for venous thromboembolism in four European countries.

BACKGROUND: The European rivaroxaban post-authorization safety study evaluated bleeding risk among patients initiated on rivaroxaban or vitamin K antagonists for the treatment and secondary prevention of venous thromboembolism in routine clinical practice. METHODS: Cohorts were created using electronic healthcare databases from the UK, the Netherlands, Germany and Sweden. Patients with a first prescription of rivaroxaban or vitamin K antagonist during the period from December 2011 (in the UK, January 2012) to December 2017 (in Germany, December 2016) for venous thromboembolism indication, with no record of atrial fibrillation or recent cancer history, were observed until the occurrence of each safety outcome (hospitalization for intracranial, gastrointestinal, urogenital or other bleeding), death or study end (December 2018; in Germany, December 2017). Crude incidence rates of each outcome per 100 person-years were computed. RESULTS: Overall, 44 737 rivaroxaban and 45 842 vitamin K antagonist patients were enrolled, mean age, 59.9-63.8 years. Incidence rates were similar between rivaroxaban and vitamin K antagonist users with some exceptions, including higher incidence rates for gastrointestinal bleeding in rivaroxaban users than in vitamin K antagonist users. Among rivaroxaban users, mortality and bleeding risk generally increased with age, renal impairment and diabetes. CONCLUSIONS: This study provides further data from routine clinical practice that broadly support safety profile of rivaroxaban for VTE indication and complement findings from previous randomized clinical trials.

Challenges and lessons learned from a long-term postauthorisation safety study programme of rivaroxaban in Europe.

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.

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.

Time Trends in Patient Characteristics of New Rivaroxaban Users with Atrial Fibrillation in Germany and the Netherlands.

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.

Safety and effectiveness of rivaroxaban for prevention of stroke in patients with nonvalvular atrial fibrillation: analysis of routine clinical data from four countries.

BACKGROUND: 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. RESEARCH DESIGN AND METHODS: 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 nonuse). Statistical analyses comparing rivaroxaban and SOC cohorts were not performed. RESULTS: 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 nonuse. Rivaroxaban use (vs nonuse) 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 to 1.52 events per 100 person-years for rivaroxaban users. CONCLUSIONS: 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.

Investigating drug safety in pregnancy based on the German Pharmacoepidemiological Research Database (GePaRD): A proof-of-concept analysis on the association between valproate and spina bifida.

PURPOSE: Large health-care databases are increasingly used for research on drug utilization and safety in pregnancy. For the German Pharmacoepidemiological Research Database (GePaRD), covering ~20% of the German population, algorithms have been developed to identify pregnancies, to estimate their date of onset and to link mothers to their babies. Using this methodology, we aimed to conduct a proof-of-concept analysis on the known association between valproate (VPA) exposure in early pregnancy and spina bifida in the exposed child. METHODS: We identified all pregnancies in GePaRD between 2006 and 2016 in women aged 12 to 50 years. To each VPA dispensation of these women, an exposure period was assigned, based on the dispensation date and the number of defined daily doses in the dispensed package. A pregnancy was classified as exposed to VPA in the critical time window if this exposure period overlapped with the first 55 days of pregnancy. Risk ratios were calculated for spina bifida in live births and induced abortions comparing VPA-exposed ones to all pregnancies. RESULTS: Overall, we identified 1 271 384 pregnancies fulfilling the inclusion criteria. Of these, 668 pregnancies (0.053%) were classified as exposed to VPA in the critical time window regarding spina bifida. An induced abortion accompanied by a diagnosis of spina bifida was observed in one of the VPA-exposed pregnancies (0.15%) and in 154 of all pregnancies (0.012%), yielding a risk ratio of 12.4 (95% confidence interval [CI]: 1.7-88.2). Out of 775 875 pregnancies ending in a live birth, 366 (0.047%) were classified as VPA exposed. A diagnosis of spina bifida was coded in 3 of 366 VPA-exposed live births (0.82%) and in 260 of all live births (0.03%), yielding a relative risk of 24.5 (95% CI: 7.9-76.0). CONCLUSIONS: Our proof-of-concept analysis based on GePaRD showed a strong association between intrauterine exposure to VPA and occurrence of spina bifida. The results are plausible and consistent with the literature, supporting the suitability of GePaRD and the developed algorithms to conduct studies on drug safety in pregnancy.

Validation of Algorithms to Identify Acute Myocardial Infarction, Stroke, and Cardiovascular Death in German Health Insurance Data.

Purpose: Validation of outcomes allows measurement of and correction for potential misclassification and targeted adjustment of algorithms for case definition. The purpose of our study was to validate algorithms for identifying cases of acute myocardial infarction (AMI), stroke, and cardiovascular (CV) death using patient profiles, ie, chronological tabular summaries of relevant available information on a patient, extracted from pseudonymized German claims data. Patients and Methods: Based on the German Pharmacoepidemiological Research Database (GePaRD), 250 cases were randomly selected (50% males) for each outcome between 2016 and 2017 based on the inclusion criteria age ≥50 years and continuous insurance ≥1 year and applying the following algorithms: hospitalization with a main diagnosis of AMI (ICD-10-GM codes I21.- and I22.-) or stroke (I63, I61, I64) or death with a hospitalization in the 60 days before with a main diagnosis of CV disease. Patient profiles were built including (i) age and sex, (ii) hospitalizations incl. diagnoses, procedures, discharge reasons, (iii) outpatient diagnoses incl. diagnostic certainty, physician specialty, (iv) outpatient encounters, and (v) outpatient dispensings. Using adjudication criteria based on clinical guidelines and risk factors, two trained physicians independently classified cases as "certain", "probable", "unlikely" or "not assessable". Positive predictive values (PPVs) were calculated as percentage of confirmed cases among all assessable cases. Results: For AMI, the overall PPV was 97.6% [95% confidence interval 94.8-99.1]. The PPV for any stroke was 94.8% [91.3-97.2] and higher for ischemic (98.3% [95.0-99.6]) than for hemorrhagic stroke (86.5% [76.5-93.3]). The PPV for CV death was 79.9% [74.4-84.4]. It increased to 91.7% [87.2-95.0] after excluding 32 cases with data insufficient for a decision. Conclusion: Algorithms based on hospital diagnoses can identify AMI, stroke, and CV death from German claims data with high PPV. This was the first study to show that German claims data contain information suitable for outcome validation.

Use of combined oral contraceptives and risk of venous thromboembolism in young women: a nested case-control analysis using German claims data.

OBJECTIVE: To compare the risk of venous thromboembolism (VTE) among young women for nine combined oral contraceptives (COCs), including progestogens with an as yet unclear risk of VTE such as chlormadinone and nomegestrol, using COCs containing levonorgestrel with low ethinylestradiol (<50 µg) as a reference. DESIGN: Case-control study nested in a cohort of new users of COCs. SETTING: German claims data. POPULATION: A total of 1166 cases of VTE matched to 11 660 controls nested in a cohort of 677 331 girls and young women aged 10-19 years with one or more COCs dispensed between 2005 and 2017 after a 1-year period without any COCs. METHODS: Confounder-adjusted odds ratios (aORs) of VTE associated with current use of the respective COCs were calculated using conditional logistic regression. MAIN OUTCOME MEASURES: Venous thromboembolism (VTE), defined as a diagnosis of pulmonary embolism or deep vein thrombosis. RESULTS: Compared with levonorgestrel with low ethinylestradiol (<50 µg), the risk of VTE was increased two-fold for COCs containing dienogest (aOR 2.23, 95% CI 1.77-2.80), cyproterone (aOR 2.15, 95% CI 1.43-3.25), chlormadinone (aOR 2.06, 95% CI 1.58-2.68), desogestrel (aOR 1.93, 95% CI 1.44-2.61) and drospirenone (aOR 1.89, 95% CI 1.41-2.55), and increased five-fold for gestodene (aOR 5.05, 95% CI 1.23-20.74). For norgestimate and nomegestrol, the point estimates suggest a two-fold increased risk (aOR 1.90, 95% CI 0.62-5.81) and 40% increased risk (aOR 1.41, 95% CI 0.52-3.81), respectively. CONCLUSIONS: Our study confirms that levonorgestrel with low ethinylestradiol (<50 µg) is the COC associated with the lowest risk of VTE and suggests that for chlormadinone the risk of VTE is two times higher, and thus in the same range as for desogestrel and drospirenone.

Characteristics of New Users of Aclidinium Bromide, Aclidinium/Formoterol, and Other COPD Medications in the United Kingdom, Denmark, and Germany.

BACKGROUND AND OBJECTIVES: Aclidinium bromide was approved in the European Union for the treatment of chronic obstructive pulmonary disease (COPD) in adult patients in 2012 and in a fixed-dose combination with formoterol in 2014. We characterised new users of aclidinium, aclidinium/formoterol and other COPD medications and evaluated off-label prescribing of these medications in three European populations. METHODS: We described demographic characteristics, comorbidities, comedications, COPD severity and off-label prescribing of new users of aclidinium, aclidinium/formoterol and other COPD medications in patients with COPD aged ≥ 40 years in the Clinical Practice Research Datalink (CPRD, UK), Danish National Health Databases, and German Pharmacoepidemiological Research Database (GePaRD) between 2015 and 2017. RESULTS: We included 17,668 new users of aclidinium (CPRD, 4871; Denmark, 2836; GePaRD, 9961) and 14,808 new users of aclidinium/formoterol (CPRD, 2153; Denmark, 2586; GePaRD, 10,069). Study patients were of similar age, except in GePaRD, where users of long-acting beta2-agonists (LABA)/inhaled corticosteroids were younger. Patients had multiple comorbidities and used multiple comedications-most frequently hypertension (50-79%) and short-acting beta2-agonists (26-84%). Aclidinium users in CPRD and long-acting anticholinergics/LABA users in Denmark and GePaRD had the highest frequency of severe/very severe COPD. Off-label prescribing of aclidinium (5.0% [CPRD]-8.9% [Denmark]) and aclidinium/formoterol (2.6% [GePaRD]-3.2% [CPRD]) was low, and the main reason was asthma without a COPD diagnosis. CONCLUSIONS: Aclidinium and aclidinium/formoterol were mostly prescribed according to label, with preference given to older patients with more severe COPD and to patients with a high prevalence of comorbidities and comedication use.

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.

Adherence and Persistence with Once-Daily vs Twice-Daily Direct Oral Anticoagulants Among Patients with Atrial Fibrillation: Real-World Analyses from the Netherlands, Italy and Germany.

BACKGROUND: Direct oral anticoagulants are available for patients with atrial fibrillation. OBJECTIVE: This study compared adherence and persistence of once-daily (QD) vs twice-daily (BID) direct oral anticoagulants in patients with atrial fibrillation. METHODS: A cohort study was conducted in three databases in the Netherlands, Italy and Germany. Patients with AF starting direct oral anticoagulants after drug approval date were included. The index date was the date of first dispensing. Study patients were restricted to those aged ≥ 18 years, ≥ 1 year database history and ≥ 1 year follow-up. Adherence to treatment was defined as the proportion of days covered ≥ 80% between the index date and the date of last dispensing of the index regimen (i.e. exposure period). The proportion of days covered was also determined during the 12-month follow-up. Persistence was defined as continuous use from index to treatment discontinuation. RESULTS: In the Netherlands, Italy and Germany, respectively, 6068, 32,260 and 167,445 patients were included. The mean age of the patients was 70, 77 and 74 years, and 31%, 40% and 61% were QD users, all respectively. Among QD/BID users, 93/90%, 88/86% and 77/58%, respectively were adherent during the exposure period. Persistence rates at 1 year in QD/BID users were 60/59%, 13/14% and 46/31%, respectively. CONCLUSIONS: Adherence to treatment was high. In Germany, adherence was markedly higher in QD users compared with BID users. In Italy and the Netherlands, these differences were marginal. Persistence was low in all countries, but discontinuation was temporary. Only in Germany, persistence was markedly lower in BID users vs QD users.

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.

Validity of hospital ICD-10-GM codes to identify anaphylaxis.

PURPOSE: Anaphylaxis (ANA) is an important adverse drug reaction. We examined positive predictive values (PPV) and other test characteristics of ICD-10-GM code algorithms for detecting ANA as used in a multinational safety study (PASS). METHODS: We performed a cross-sectional study on routine data from a German academic hospital (2004-2019, age ≥ 18). Chart review was used for case verification. Potential cases were identified from the hospital administration system. The main outcome required at least one of the following: any type of specific in-hospital code (T78.2, T88.6, and T80.5) OR specific outpatient code in combination with a symptom code OR in-hospital non-specific code (T78.4, T88.7, and Y57.9) in combination with two symptom codes. PPV were calculated with 95% confidence interval. Sensitivity analyses modified type of codes, unit of analysis, verification criteria and time period. The most specific algorithm used only primary codes for ANA (numbers added in brackets). RESULTS: Four hundred and sixteen eligible cases were evaluated, and 78 (37) potential ANA cases were identified. PPV were 62.8% (95% CI 51.1-73.5) (main) and 77.4% (58.9-90.4) (most specific). PPV from all modifications ranged from 12.9% to 80.6%. The sensitivity of the main algorithm was 66.2%, specificity 91.5%, and negative predictive value 92.6%. Corresponding figures for the most specific algorithm were 32.4%, 98.0%, and 87.0%. CONCLUSIONS: The PPV of the main algorithm seems of acceptable validity for use in comparative safety research but will underestimate absolute risks by about a third. Restriction to primary discharge codes markedly improves PPV to the expense of reducing sensitivity.

Use of intravenous iron and risk of anaphylaxis: A multinational observational post-authorisation safety study in Europe.

PURPOSE: This post-authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non-dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.8 per 10 000 first treatments. METHODS: Cohort study of IV iron new users, captured mostly through pharmacy ambulatory dispensing, from populations covered by health and administrative data sources in five European countries from 1999 to 2017. Anaphylaxis events were identified through an algorithm that used parenteral penicillin as a positive control. RESULTS: A total of 304 210 patients with a first IV iron treatment (6367 iron dextran), among whom 13-16 anaphylaxis cases were identified and reported as a range to comply with data protection regulations. The pooled unadjusted incidence proportion (IP) ranged from 0.4 (95% confidence interval [CI], 0.2-0.9) to 0.5 (95% CI, 0.3-1.0) per 10 000 first treatments. No events were identified at first dextran treatments. There were 231 294 first penicillin treatments with 30 potential cases of anaphylaxis (IP = 1.2; 95% CI, 0.8-1.7 per 10 000 treatments). CONCLUSION: We found an IP of anaphylaxis from 0.4 to 0.5 per 10 000 first IV iron treatments. The study captured only a fraction of IV iron treatments administered in hospitals, where most first treatments are likely to happen. Due to this limitation, the study could not exclude a differential risk of anaphylaxis between iron dextran and iron non-dextrans. The IP of anaphylaxis in users of penicillin was consistent with incidences reported in the literature.

Persistence and adherence to non-vitamin K antagonist oral anticoagulant treatment in patients with atrial fibrillation across five Western European countries.

AIMS: To assess persistence and adherence to non-vitamin K antagonist oral anticoagulant (NOAC) treatment in patients with atrial fibrillation (AF) in five Western European healthcare settings. METHODS AND RESULTS: We conducted a multi-country observational cohort study, including 559 445 AF patients initiating NOAC therapy from Stockholm (Sweden), Denmark, Scotland, Norway, and Germany between 2011 and 2018. Patients were followed from their first prescription until they switched to a vitamin K antagonist, emigrated, died, or the end of follow-up. We measured persistence and adherence over time and defined adequate adherence as medication possession rate ≥90% among persistent patients only. RESULTS: Overall, persistence declined to 82% after 1 year and to 63% after 5 years. When including restarters of NOAC treatment, 85% of the patients were treated with NOACs after 5 years. The proportion of patients with adequate adherence remained above 80% throughout follow-up. Persistence and adherence were similar between countries and was higher in patients starting treatment in later years. Both first year persistence and adherence were lower with dabigatran (persistence: 77%, adherence: 65%) compared with apixaban (86% and 75%) and rivaroxaban (83% and 75%) and were statistically lower after adjusting for patient characteristics. Adherence and persistence with dabigatran remained lower throughout follow-up. CONCLUSION: Persistence and adherence were high among NOAC users in five Western European healthcare settings and increased in later years. Dabigatran use was associated with slightly lower persistence and adherence compared with apixaban and rivaroxaban.

Characterization of pregnancies exposed to St. John's wort and their outcomes: A claims data analysis.

Little is known about the utilization of St. John's wort (Hypericum perforatum L.) during pregnancy. In Germany, certain preparations of St. John's wort can be reimbursed by statutory health insurances, facilitating to investigate exposure to St. John's wort based on claims data. We therefore aimed to characterize pregnancies exposed to St. John's wort and to explore potential malformations in the babies. Using claims data from the German Pharmacoepidemiological Research Database (GePaRD), pregnancies exposed to St. John's wort during at least one trimester between 2006 and 2016 and the corresponding babies were identified. Exposure was identified via outpatient dispensations. Pregnancies were characterized regarding timing of exposure, use of other antidepressants, pregnancy outcomes and the occurrence of major malformations in the babies (not considering codes for musculoskeletal and other malformations due to low data quality in this regard). Out of 496 pregnancies with a dispensation of St. John's wort during pregnancy, 420 (85 %) had a dispensation during the first trimester. There was a dispensation of other antidepressants before pregnancy in 21 % (during pregnancy: 12 %). Eleven percent of pregnancies ended in non-live births. In 312 babies linked to 305 pregnancies, major malformations were coded in 18 babies (5.8 %), of which 17 were exposed in the first trimester. The crude relative risk of major malformations for babies exposed during the first vs. the second or third trimester only was 3.56 (0.48-26.17). Our results suggest that only in a minority of pregnancies, St. John's wort is used as an alternative to other antidepressants. Even though the relatively high rates of non-live births and major malformations after exposure to St. John's wort during the first trimester need to be interpreted with caution, the findings are striking and generate hypotheses that merit further investigation.

Corrigendum: Estimating the Beginning of Pregnancy in German Claims Data: Development of an Algorithm With a Focus on the Expected Delivery Date.

[This corrects the article DOI: 10.3389/fpubh.2020.00350.].

Estimating the Beginning of Pregnancy in German Claims Data: Development of an Algorithm With a Focus on the Expected Delivery Date.

Background: Estimating the beginning of pregnancy is crucial when studying drug safety in pregnancy, but important information in this regard, such as the last menstrual period (LMP), is generally not recorded in claims databases. The beginning of pregnancy is therefore usually estimated by subtracting a median length of pregnancy from the date of birth. Due to the variability in pregnancy lengths, this might result in non-negligible errors. German claims data may offer the possibility to estimate the beginning of pregnancy more precisely based on the expected delivery date (EDD) which can be coded once or more often during a pregnancy. Purpose: To estimate the beginning of pregnancy in German claims data focusing on the potential of the expected delivery date (EDD). Methods: We included data of all pregnancies in women aged 12-50 years ending in a live birth between 2006 and 2015 identified in the German Pharmacoepidemiological Research Database (GePaRD). We assessed the number of coded EDDs per pregnancy and the concordance if ≥ 2 EDDs were coded. We estimated the beginning of pregnancy by subtracting 280 days from the EDD or the most frequent EDD (in case of discordant EDDs). To examine plausibility, we determined the distribution of pregnancy lengths and assessed whether the gestational age at which prenatal examinations were coded was plausible. For pregnancies without EDD, the beginning was estimated by subtracting the respective observed median lengths of pregnancy for preterm births, term births, and births after due date from the actual dates of birth. Results: In 82.4% of pregnancies, at least one EDD was available (thereof 6.1% with only one EDD and 80.9% with ≥ 2 EDDs that were all concordant). The maximal difference between discordant EDDs was in median 5 days (interquartile range: 3-7 days). Based on the EDD, the median length of pregnancy was 276 days for term births and in 84.7% of pregnancies the second antibody screening test was performed in the recommended interval ± 2 weeks. In pregnancies without EDD the respective proportion was 84.9%. Conclusions: By using the EDD, the beginning of pregnancy can plausibly be estimated in German claims data.

Rationale and design of a European epidemiological post-authorization safety study (PASS) program: rivaroxaban use in routine clinical practice.

BACKGROUND: Rivaroxaban is a highly selective factor Xa inhibitor approved for use in Europe for multiple indications. STUDY DESIGN AND METHODS: The European rivaroxaban epidemiological post-authorization safety study (PASS) program consists of seven complementary observational studies. For four of the studies, data are obtained from health-care databases in the UK, the Netherlands, Germany, and Sweden. These database studies describe patterns of rivaroxaban use and patient characteristics over time, and investigate safety and effectiveness outcomes in new users of rivaroxaban using a cohort analysis and nested case-control analysis. To put these results in context, safety outcomes are also analyzed in new users of standard of care. In addition, a modified prescription event monitoring study conducted in the early post-launch phase in primary care, and two specialist cohort event monitoring studies that investigated rivaroxaban use in the secondary care hospital setting, systematically collected drug utilization and safety data via questionnaires completed by health-care professionals in the UK. DISCUSSION: The European rivaroxaban epidemiological PASS is a comprehensive program of complementary studies generating evidence from patients treated in routine clinical practice that will expand our understanding of the risk-benefit profile of rivaroxaban.

Individual Antidepressants and the Risk of Fractures in Older Adults: A New User Active Comparator Study.

OBJECTIVE: To determine the risk of hip-pelvis and other non-vertebral fractures in older adults using antidepressants (ADs). METHODS: We conducted a case-control study nested in a cohort of new users of ADs aged ≥65 years without prior hip-pelvis or other non-vertebral fractures, identified in the German Pharmacoepidemiological Research Database (GePaRD) during 2005-2014. Cases were patients first hospitalized for hip-pelvis or other non-vertebral fractures. Up to 100 controls per case were selected using incidence density sampling. AD use was ascertained at index date (ID) based on the supply of last dispensing. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression with current users of mirtazapine as reference (active comparator). RESULTS: A total of 39,853 cases of hip-pelvis fracture (80% women, median age 81 years) and 31,577 cases of other fractures (84% women, median age 79 years) were matched to >3 million controls. For hip-pelvis fracture, aORs in current users were about 1.3 with little variation between individual ADs, ranging from 1.33 for citalopram (95% CI 1.27-1.39) to 1.28 for amitriptyline (1.21-1.35). For other fractures, the aORs were highest in current users of citalopram (1.50; 1.42-1.58) and duloxetine (1.54; 1.39-1.71) and lowest for amitriptyline (1.18; 1.11-1.26) and trimipramine (1.16; 1.03-1.29). For all examined ADs, the aORs were higher for other fractures than for hip-pelvis fracture. CONCLUSION: The risk of fractures varies between ADs, but for most agents is higher than the risk for mirtazapine. When treating older adults with ADs, prescribers should carefully consider the risk profile of individual ADs regarding fractures, which are a major health problem in this population.