Drug utilization analysis of osteoporosis medications in seven European electronic health databases.

We studied the characteristics of patients prescribed osteoporosis medication and patterns of use in European databases. Patients were mostly female, older, had hypertension. There was suboptimal persistence particularly for oral medications. Our findings would be useful to healthcare providers to focus their resources on improving persistence to specific osteoporosis treatments. PURPOSE: To characterise the patients prescribed osteoporosis therapy and describe the drug utilization patterns. METHODS: We investigated the treatment patterns of bisphosphonates, denosumab, teriparatide, and selective estrogen receptor modulators (SERMs) in seven European databases in the United Kingdom, Italy, the Netherlands, Denmark, Spain, and Germany. In this cohort study, we included adults aged ≥ 18 years, with ≥ 1 year of registration in the respective databases, who were new users of the osteoporosis medications. The study period was between 01 January 2018 to 31 January 2022. RESULTS: Overall, patients were most commonly initiated on alendronate. Persistence decreased over time across all medications and databases, ranging from 52-73% at 6 months to 29-53% at 12 months for alendronate. For other oral bisphosphonates, the proportion of persistent users was 50-66% at 6 months and decreased to 30-44% at 12 months. For SERMs, the proportion of persistent users at 6 months was 40-73% and decreased to 25-59% at 12 months. For parenteral treatment groups, the proportions of persistence with denosumab were 50-85% (6 month), 30-63% (12 month) and with teriparatide 40-75% (6 month) decreasing to 21-54% (12 month). Switching occurred most frequently in the alendronate group (2.8-5.8%) and in the teriparatide group (7.1-14%). Switching typically occurred in the first 6 months and decreased over time. Patients in the alendronate group most often switched to other oral or intravenous bisphosphonates and denosumab. CONCLUSION: Our results show suboptimal persistence to medications that varied across different databases and treatment switching was relatively rare.

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.

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.

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.

Risk Profiles of New Users of Oral Anticoagulants Between 2011 and 2019 in Germany.

Purpose: Over the last decade, the use of direct oral anticoagulants (DOACs) has strongly increased. We aimed to describe and compare risk profiles including potential changes over time among persons with non-valvular atrial fibrillation initiating treatment with different DOACs or phenprocoumon (vitamin K antagonist) between 2011 and 2019 in Germany. Patients and Methods: Using the German Pharmacoepidemiological Research Database (GePaRD; claims data of ~20% of the German population), we identified persons with a first dispensing of phenprocoumon or a DOAC and a diagnosis of non-valvular atrial fibrillation between August 2011 and December 2019. We described the morbidity of included patients prior to treatment initiation, stratified by year of treatment initiation. Results: Overall, we included 448,028 new users (phenprocoumon: N = 118,117, rivaroxaban: N = 130,997, apixaban: N = 130,300, edoxaban: N = 38,128, dabigatran: N = 30,486). Comparing new DOAC users in 2019, the proportion with prior ischemic stroke was highest for dabigatran (17%) and lowest for rivaroxaban (8%). The proportion with prior major bleeding was also highest for dabigatran (25%) and lowest for edoxaban (20%). New users of apixaban were oldest and, eg, showed the highest prevalence of congestive heart failure. Changes over time were most pronounced for phenprocoumon. For example, among persons initiating phenprocoumon in 2012 vs 2019, the proportion with prior major bleeding increased from 18% to 35%; the proportion with renal disease increased from 20% to 36% and the proportion with liver disease from 18% to 24%. Conclusion: This study demonstrated differences in risk profiles between new users of different oral anticoagulants and substantial changes over time among new phenprocoumon users. These differences have to be considered in head-to-head comparisons of these drugs based on observational data, especially regarding potential unmeasured confounding.

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.

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.

Bronchial muscle peristaltic activity in the fetal rat.

Aside for the potential for tonic contraction, the airway smooth muscle exhibits intermittent phasic rhythmic activity that may contribute to lung growth during fetal life. Therefore, we examined 4th generation rat 18-22 d gestation fetal, 4-6 d of age newborn and adult bronchial ring from Sprague Dawley rats to compare differences in smooth muscle function. We hypothesized that phasic contractions were greatest before birth. Bronchial muscle spontaneous rhythmic contractions were greatest in the fetus and absent in the adult. In response to KCl stimulation, the fetal bronchial smooth muscle only developed tonic force that was 3.5 +/- 0.6 and lower than measured in the newborn 9.0 +/- 0.3 and adult 13.7 +/- 1.4 mN/mm2. The thromboxane A2 analogue U46619 induced tonic and phasic muscle contractions and the amplitude and frequency of the phasic contractions were greater in the fetus as compared with the adult and increased with gestational age. The U46619-induced rhythmic contractions were abrogated by ryanodine, thapsigargin and reduction of extracellular Na+, suggesting intracellular Ca2+ dependence and involvement of the Na+/Ca2+ exchanger. The inward rectifier K+ blocker BaCl2 induced phasic contractions in unstimulated fetal, but not adult bronchial muscle of the same amplitude and frequency as for the spontaneous and U46619-induced ones. We conclude that the airway smooth muscle phasic activity is greatest in the fetus and tends to disappear post-natally with age suggesting an in utero role during lung development.