Background:
An imbalance in the incidence of serious CV events, driven by events of MI and stroke, was observed with romosozumab in the alendronate ( ALN) – controlled study 20110142 ( ARCH) after 12 months of treatment. No imbalance was observed in the placebo-controlled study 20070337 ( FRAME) after 12 months of treatment. Serious CV events of MI and stroke are determinded an identified risk in the European Union ( EU) – Risk Management Plan ( RMP).
Research questions and objectives: The overarching objective of this study is to characterize the risk of serious CV events of MI and stroke and all-cause mortality including CV death associated with the use o romosozumab, in comparison with other available OP medications in routine clinical practice in Europe.
Specifically, the study will provide further understanding on the following objectives: 1- to assess the incidence rate (IR) of serious CV events ( MI and stroke) and all-cause mortality including CV death in romosozumab users in the indicated population in Europe as per the summary of products characteristics ( SmPC), and in cohorts of users of other OP medications who would also fulfil the indication (contraindications for romosozumab in Europe; 2- to assess the IR of serious CV events ( MI and stroke) and all-cause mortality including CV death in romosozumab users in the indicated population in Europe spoer the SmPC and amongst users of other OP medications similar to the indicated population for romosozumab in Europe as per the SmPC, stratified by age, previous use of OP medications and by prespecified key CV risk factors; 3- to assess the comparative risk of CV events ( MI and stroke) and all-cause mortality including CV death in romosozumab users in the indicated population in Europe as per the SmPC to users of ALN ( active comparator) with similar baselien characteristics.
Methodology: study design: multinational-multidatabase cohort study of new users of romosozumab and new users of other OP medications. study period is expected to last 6 years ( 2020-2026).
Population: the study population comprises all women from the 7 participating databases with severe OP who are dispensed or prescribed an OP medication of interest for the first time ( new users ) during the study period, have been continiously registered in the data source for at least 12 months prior the the first recorded dispensing/prescription of the OP medication of interst, and are at least 50 years of age on the date of the first dispensing/prescription of the OP medication of interest. Women with diagnosis of cancer ( any except basal cell skin cancer) or paget disease at any time before treatment initiation will be excluded. New users will be followed for a maxium of 24 months from index therapy inititation ( index date). Two Follow-up periods will be included for the estimation of CV IRs: an Exposure-based follow-up period and a fixed ( first exposure carried forward) follow-up period.
For the exposure-based analysis, participants will be followed until the occurrence of the CV event of interest, discontinuation of the study drug of interest, switch or addition of any otherOP medication ( except Calcium/vitamin D supplements), lost to follow-up, death, end of the 12 months after therapy initiation (as per the romosozumab SmPC), or end of the study period/data extraction date. For the Fixed Follow-up Period, participants will be followed in their respective cohorts until lost to follow-up, CV event of interest, death or end of the study period. Variables: the OP medication of interest include romosozumab and other OP medications, such as ALN (primary active comparator), other oral bihposphonates (ibandronate or risedronate at doses indicated for OP treatment), intravenous (iv) biphosphonates (zoledronate or ibandronate at doses indicated for OP treatment), denosumab (at the dose indicated for OP treatment) and teripartide.
Primary outcome is major adverse cardiac event(s) (MACE-2) (first occurrence of death [all cause], MI or stroke). Secondary outcomes are MI, stroke, death due to CV cause, all-cause mortality and MACE-1 (first occurrence of death due to CV causes, MI or stroke). Other covariates and potential confounding factors will be identified at cohort entry (index date) based on the patients’ records in the previous 12 months (baseline period), and will include general patient characteristics, CV risk facgtors, markers of OP severity, and use of other medications.
Data sources: This study will be conducted using routinely collected data from different data sources that participate in the EU-ADR Alliance, with the addition of databases from the UK (Clinical Practice Research Datalink [CPRD] GOLD), Germany (German PHarmacoepidemiological Research Database [GePard]), and France (Système National Des Données de Santé [SNDS] database). Participants form 7 European countries will provide heterogeneous and representative data on the safety of romosozumab as well as ensuring sufficient statistical power for the study.
Study size: Feasibility estimates demostrate the capability of the ocnsortium and the data sources to capture a sufficient sample of patients in each OP medication group. The number of romosozumab users and comparator users needed to obtain an alpha risk of 0.05 with 90% power in a 1:3 (romosozumab:comparator) matched cohort analysis for different scerarios of incidence of CV events and hazard ratio (HR) were calculated. In the worst-case scenario of IRs of 1 per 100 person-year and a 2-fold relative increase in risk, 1,450 romosozumab users (and 4,350 users of the active comparator) would be required.
Data analysis: The IRs of CV events of interest for each OP medication will be calculated for the 2 Follow-up Periods. Incidence rates and 95% conficence intervals (CIs) of CV events of interest will be calculated for each study drug using a Poisson model.
For the Fixed Follow-up Period, IR of patients with CV events of interest will also be reported.
The CV event/s rates (as in objective 1 and 2) for each study drug will be provided stratified by key CV risk factors. For objective 3 (the comparative safety analysis), the Cox regression model stratified by matched sets will be used to calculate HRs and 95% CIs for eath safety endpoint (MI, stroke, MACE-1 and MACE-2).
Measures for reducing confounding by indication will be implemented including propensity score matching as well as negative control outcome analyses to identify unobserved confounding. If required, additional analysis will be conducted to assess the effects of potential biases related to insufficient control for confounding/channeling bias: (i) empirical calibration using negative control outcomes; (ii) self-controlled case series (SCCS) and (iii) instrumental variable analysis.

Background: As women diagnosed with breast cancer are living longer, attention to the impact of known and suspected cardiotoxicities associated with breast cancer treatment is increasing. Large scale, long duration observational studies are needed for research in this area. SIDIAP is planning to link primary and secondary clinical data to cancer treatment data for this purpose.
Hypotheses and objectives: We aim to compare use of systemic chemotherapies in breast cancer patients with prior cardiovascular disease or risk factors to patients at lower risk of cardiovascular disease. We will also characterise the new linked data resource.
Methodology (design, setting, participants): This cross-sectional observational study will link primary care health records for female breast cancer patients in the SIDIAP database with hospital discharge and cancer treatment data. The study period is 2011 to 2017.
Measurements:
Exposure: cardiovascular disease risk (low vs. prior cardiovascular disease; low vs. primary)
Analysis populations: Analysis populations will be defined according to treatment guidelines ICOPraxis in Institut Català d?Oncologia (ICO) in Catalonia
Primary outcomes: Systemic chemotherapy agents administered in first year
Secondary outcomes: dose at initiation, cumulative dose
Covariates: age at diagnosis, socioeconomic status, cardiovascular risk factors (secondary risk analysis), type of prior cardiovascular disease (secondary risk analysis), calendar time
Statistical analysis: Descriptive analyses and logistic regression models will be performed.
Expected outcomes: Peer reviewed journal publication. Linkage of SIDIAP and ESPOQ data bases.
Applicability and relevance: Our study will improve understanding of how knowledge and guidelines relating to the toxicity of systemic chemotherapies is being translated into practice, and inform future studies investigating the likely future burden of CVD in breast cancer patients. It will also provide the basis for future studies needing both SIDIAP and cancer treatment data.

Antecedentes: aunque se sabe que la osteoartritis (OA) está relacionada con varias comorbilidades, la asociación entre la OA y el cáncer rara vez se ha estudiado.

Hipótesis: la OA puede tener asociaciones heterogéneas con cánceres comunes.

Objetivos: Estimar la asociación entre la OA de rodilla y cadera y los cánceres específicos en adultos.

? Study Title
Estimating Short-Term and Long-Term Direct Economic Burden Associated with Osteoporotic Fractures
? Background and Rationale
Osteoporotic fractures (OFs) among adults are considered an important public health concern, with up to 50% of women and 22% of men over the age of 50 years experiencing at least one fragility fracture in their lifetime. Additionally, the risk of osteoporotic fractures increases with age, especially in postmenopausal women among whom decreased estrogen levels are associated with decreased bone mineral density (BMD). Osteoporotic fractures are associated with significant burden both in formal (e.g. hospitalizations, rehabilitative services, long-term care) and informal (e.g. care provided by family and friends) care settings, and increased mortality. Considering the total burden of OFs to both patient and society, it is important to better understand the short- and long-term direct healthcare impact in order to enhance osteoporosis management in the contemporary care setting. This study will focus on evaluating the direct economic burden of OFs, while a companion protocol will evaluate the indirect and humanistic burden of OFs. Moreover, the outputs from the proposed study will inform policy makers, clinicians, and patients about the multi-national burden of OFs in women, and help payers and clinicians understand the importance of treatment advances that can reduce the risk of osteoporotic fractures. This study will have the advantage of estimating the direct economic burden in six countries using the same study population composition and same time period rather than previous studies that have varying study population characteristics at varying time periods.

? Research Question and Objectives
The study aims to evaluate the direct economic burden of OFs in women aged 50 years or older in the short-term (index fracture date to 12 months) and long-term (one year to five years) following the date of the first recorded osteoporotic fracture.
Study Objectives
1. Estimate the short-term and long-term direct, post-index healthcare resource utilization (HCRU) and costs in women who experienced an incident OF and in a matched cohort of women free of any OF.
2. Estimate the short-term and long-term direct HCRU and costs pre- versus post-fracture (before and after osteoporotic fracture) in women who experienced an incident OF.
? Study Design/Type
This is a multi-national, retrospective cohort study to assess direct economic burden of OF between 2013-2018 in women aged 50 years or older in 6 countries (Australia, France, Germany, Japan, Spain, and USA). The direct all-cause HCRU and cost experience of women with an incident OF in each country will be compared with matched women without an OF (i.e. non-OF cohort) during the study period. Because of differences in healthcare systems, provision of services and costs across countries, outcomes will be reported by individual country. Women with an osteoporotic fracture will initially be matched to women in the non-OF cohort using the same birth month and year as the women with an osteoporotic fracture, then matched 1:1 on selected variables as described in Section 9.1.3. Additionally, among women with an OF, pre-fracture and post-fracture HCRU and costs will be compared. Regional or national electronic medical records (EMR), registries, or claims databases will be used in each country as described in section 10.1. For example, the PharMetrics Plus, anonymised patient-level claims database including primary and secondary care data from US commercial payers, will be used for the USA.
The study design is depicted in Figure 1 above; the following time periods/dates have been defined:
1. Index date: The index date for the OF cohort corresponds to the calendar date of the first record of an OF (i.e. incident OF) between January 1, 2013 and November 30, 2018. The index dates of the women with osteoporotic fracture will then be assigned to the corresponding matched non-OF women, in order to ensure there are no temporal differences in the comparisons between the populations.
2. Pre-index period: The pre-index period (i.e. baseline period) corresponds to the 18 months preceding the index date for both the OF and the non-OF cohort. Women must have 18 months of continuous enrollment in the database pre-index to ascertain osteoporotic fracture-free status and comorbidity and medication history.
3. Follow-up period: The follow-up period corresponds to the period extending from the earliest of index date up to December 31, 2018 (study end date), death, fracture event in non-OF woman, or lost to follow-up (drop out of the database). For woman included in the study, the follow-up period can range from a minimum of one month up to six years from the index date.
? Study Population
The study population is women aged ?50 years with or without an osteoporotic fracture. This study will be conducted in six countries: United States, Australia, France, Germany, Spain and Japan.

? Patient Eligibility
Inclusion Criteria:
OF cohort:
1. Women aged ?50 years when experiencing an incident osteoporotic fracture at the following skeletal sites: hip, vertebral (spine), forearm (radius, ulna), humerus, pelvis, proximal femur, tibia, fibula, ribs, clavicle, scapula, and ankle between January 1, 2013 and November 30, 2018.
2. Continuously enrolled in the database for at least 18 months prior to index date and at least 1 month after index date.
3. No osteoporotic fracture in the pre-index period (i.e. 18 months prior to index fracture)
Non-OF cohort:
1. Women aged ?50 years and with no record of osteoporotic fracture in the pre-index period (i.e. 18 months prior to assigned index date).
2. Continuously enrolled in the database for at least 18 months prior to index date and at least 1 month after assigned index date.
Exclusion Criteria for both cohorts:
1. Record of participation in a clinical trial pertaining to an osteoporotic treatment ?18 months before the index date.
2. Cancer (except non-melanoma skin cancer) during the study period (July 1, 2011-December 31, 2018). Patients with cancer will be excluded because of the high healthcare resource utilization and costs of cancer care as well as effect of cancer and chemotherapeutic agents on bone.
3. Paget’s disease of the bone, osteitis deformans, and osteopathies or metabolic bone diseases (e.g., osteomalacia, hyperparathyroidism, osteogenesis imperfecta) during the study period (July 1, 2011-December 31, 2018). Patients with other bone conditions will be excluded to ensure that the outcomes are associated with osteoporosis and not other bone diseases.

? Matching criteria
Women without OF will be matched to women with OF. Women in the non-OF cohort will first be matched to women with OF using their birth month and year. The index date of the women with fracture (i.e. fracture date) will then be assigned to the corresponding matched non-OF women. After identifying an age-matched group of non-OF patients for each OF patient, the closest matching non-OF woman will be identified through propensity score matching using important confounders (e.g. geographic region, race/ethnicity, total months since index date (fracture date), pre-index glucocorticoid use, pre-index hormone replacement therapy, pre-index anti-osteoporosis drug use, selected comorbidities, and pre-index hospitalizations. The OF and non-OF women will be matched 1:3. If a non-OF woman has a fracture during follow-up, then she will be censored on the date of her fracture. A 1:3 matching will be used to optimize follow-up time of women with OF because a non-OF woman may fracture and be censored before the end of follow-up of the matched woman with OF.
? Variables
Study Outcomes
? Direct all-cause healthcare resource utilization: HCRU will include any resource/services directly provided by the healthcare system in each relevant country, including hospitalisations, emergency room (ER) visits, physician visits, diagnostic and/or reimbursed procedures, and prescriptions. Physical and/or occupational therapy services also will be reported.
? Direct all-cause healthcare costs will be estimated using country-specific costs, and include total direct costs (medical + pharmacy), total medical costs (inpatient + outpatient), hospitalizations, ER, physician, and outpatient pharmacy costs.
? Study Sample Size
The half-length of the 95% confidence intervals (CI) for estimated direct costs was calculated based on mean total costs from the multi-national study of Svedbom et al 2013. The half length of the CI was estimated to be 536 for a sample size of 2,000 and 107 for a sample size of 50,000 for the first year cost of approximately $14,335. The half length of the CI was estimated to be 160 (sample size of 2,000) and 71 (sample size of 50,000) for the fifth year cost of approximately $4,421. The half length for the intervening years since fracture (i.e. 2-4 years) fell between the ranges for the first and fifth year. It is estimated that the number of incident fractures may range from about a low of 16,000 in Australia to more than 140,000 in Spain. Due to the large sample size, the CIs will be narrow, and it is believed that the estimate of direct costs will be with very small estimate error and reliable.
? Data Analysis:
All analyses will be country-specific and will not be combined across countries due to differences in healthcare systems. Demographics, baseline clinical characteristics, and pre-index direct all-cause HCRU and costs will be reported for OF and non-OF groups using number and percent within category for categorical variables, and mean (standard deviation [SD]) with 95% confidence interval or median (interquartile range [IQR]), minimum and maximum values for continuous variables as appropriate. Methods for dealing with missing data such as multiple imputation or last observation carried forward (LOCF) will not be applied, and the number with missing data reported.
To evaluate direct all-cause HCRU and costs among the propensity score matched women who experienced an OF and those who did not, descriptive measures including the mean (SD), median (IQR), and range (minimum, maximum) will be reported. Costs will be log-transformed to diminish the effect of outliers. Direct HCRU and costs will be reported by the year since index date (fracture date) (e.g. ?1 year, >1 to ?2 years, >2 to ?3 years, >3 to ?4 years, >4 to ?5 years since index date) and include all patients alive at the start of each annual period to assess short-term and long-term economic burden of OF. The main outcome is the difference between direct all-cause HCRU and costs in OF and non-OF cohorts (incremental costs). Likewise, the mean HCRU and costs among women with an OF will be compared between 1-year pre-fracture versus each year (1 to 5) post-fracture. Rate of HCRU will be calculated for each year since index date (fracture date) as the number of utilizations divided by follow-up time in the year. The rate will be reported for each individual healthcare resource type. Also, the proportion of women with at least 1 utilization for each resource type (e.g. had at least 1 hospitalization, at least 1 ER visit) will be reported
Comparisons will be made for all osteoporotic fracture types combined as well as by individual osteoporotic fracture types. Differences in HCRU and costs between OF and non-OF cohorts and pre-index versus post-index among OF women will be assessed using regression modelling. A linear regression model with log-transformed costs or gamma regression will be considered. Outcomes will be stratified by residence (i.e. community-dwelling or not) at index date, and also by occurrence of subsequent osteoporotic fracture among OF women during follow-up (yes/no).

The European Health Data and Evidence Network (EHDEN) invites Data partners in Europe to apply for funding to map their health data to the OMOP common data model (CDM). The ambitions of the EHDEN project are high. We aim to standardise more than 100 million patient records across Europe from different geographic areas and different data sources. Mapping of such data to the OMOP CDM will facilitate their use for a variety of purposes, enhancing and accelerating research and healthcare decision-making for global benefit.

The Agency considers it requires a study to investigate exposure and use patterns of H2-receptor antagonists-containing medicinal products authorised in the European Union (EU).
The study should be carried out in at least five European countries with ideally equal spread across Western, Southern, Northern and Eastern countries and balanced representation of European healthcare services and setting with the following objectives:
1. To determine drug utilisation and prescription patterns of medicinal products containing H2-receptor antagonists (ATC codes: A02BA01 (cimetidine), A02BA02 (ranitidine), A02BA03 (famotidine), A02BA04 (nizatidine), A02BA06 (roxatidine), A02BA07 (ranitidine bismuth citrate), A02BA08 (lafutidine), A02BA51 (cimetidine, combinations) and A02BA53 (famotidine, combinations) by substance over a minimum period of five years (preferably more) including up to 2018 or more recent data. This study should give particular focus to:
a. Prescribing of medicinal products containing H2-receptor antagonists by incident and prevalent use by year, by indication (i.e. gastro-oesophageal reflux disease (GERD), gastric and duodenal ulcer, ulcer associated with H. pylori, Zollinger-Ellison syndrome), by age group, by gender, by dose, by formulation, by duration, by cumulative exposure and by country and data source;
b. To determine, in so far as is possible, comorbidity of renal impairment in patients using H2-receptor antagonist containing medicinal products.