Carlen Reyes Reyes

Antecedentes y objetivos:
Este estudio busca mejorar la identificación de pacientes en riesgo de eventos adversos relacionados con la medicación potencialmente inapropiada (MPI) en atención primaria. Las prácticas actuales no consideran de forma integral el perfil de exposición, definido por el número, tipo y duración de la exposición a MPI.
Metodología:
Se diseñará una escala de riesgo (alto, medio o bajo) de caídas, fracturas, hospitalizaciones o muerte en función del perfil de exposición a los medicamentos del listado STOPPFall, y se evaluará el impacto de una intervención de toma de decisiones compartidas para la deprescripción. El estudio comprende dos fases: (1) un observacional retrospectivo (2010–2025) con datos de SIDIAP en pacientes de al menos 65 años, donde se analizarán incidencias de eventos adversos y su asociación con MPI mediante cohortes y casos-control anidados, y se elaborará la escala de riesgo; y (2) un ensayo clínico cuasiexperimental en dos centros de salud de Barcelona, con 198 pacientes con riesgo medio o alto de padecer uno de los eventos adversos por las MPI. La intervención constará de una formación sobre decisiones compartidas para pacientes y médicos, con seguimiento de seis meses para medir el efecto en la reducción de MPI y eventos adversos.
Determinaciones:
En el estudio observacional, la variable de exposición será la dispensación de MPI de la lista STOPPFall, creando perfiles según número, tipo y tiempo de exposición en el año previo al evento. Las variables de resultado incluirán hospitalización, mortalidad, caídas y fracturas. Otras variables abarcarán características sociodemográficas, índice de comorbilidad de Charlson, hábitos tóxicos, IMC, fármacos concomitantes, visitas a atención primaria e índice de deprivación socioeconómica, considerando como confusores las patologías y medicamentos asociados a mayor riesgo. En el ensayo cuasiexperimental, la variable de exposición será pertenecer al grupo intervención o control. La variable principal de resultado será la reducción en número o dosis de MPI, y las secundarias incluirán caídas, fracturas, hospitalización y mortalidad. Se recogerán además datos sociodemográficos, hábitos de vida, comorbilidades, medicaciones activas y uso de recursos sanitarios.
Análisis estadístico:
Para el estudio observacional se realizará un análisis descriptivo de variables sociodemográficas y clínicas, así como de la exposición a MPI. Se estimará la incidencia anual de eventos adversos (hospitalización, mortalidad, caídas y fracturas) en cohortes, y se aplicarán estudios de casos y controles anidados mediante emparejamiento (optmatch) y modelos de regresión logística condicional, ajustando por edad, sexo, comorbilidad y otros factores de confusión. En la cohorte de expuestos a MPI, se evaluará el riesgo según número, tipo y tiempo de exposición, clasificando a los pacientes en categorías de riesgo bajo, medio y alto. La comparación de grupos se realizará con Ji-Cuadrado y ANOVA, estableciendo la significación en p<0,05. En el ensayo cuasiexperimental se describirán las variables basales y se compararán los grupos de intervención y control a los seis meses en cuanto a número, tipo y dosis de MPI, así como en caídas, fracturas, hospitalizaciones y mortalidad. Se utilizarán pruebas Ji-Cuadrado y t de Student, y se construirá un modelo de regresión logística para identificar factores asociados con la reducción de la exposición a MPI. Se considerará la intervención efectiva si logra disminuir el número o la dosis prescrita de MPI. Resultados esperados, aplicabilidad y relevancia: Se espera que el proyecto permita identificar a la población mayor en mayor riesgo de eventos adversos mediante una escala de riesgo y que, a través de estrategias de toma de decisiones compartidas, se reduzca el uso de MPI. Esto debería traducirse en una menor frecuencia de caídas, fracturas y hospitalizaciones, con beneficios directos para pacientes y familias, así como en una reducción de los costes sanitarios. Además, la integración de estrategias educativas en la práctica clínica puede establecer un modelo para futuras intervenciones en seguridad farmacológica en personas mayores.

El objetivo de este estudio es 1. Describir las actitudes y preferencias de los pacientes en cuanto a la medicación, incluido el modo (oral frente a inyectable) y la frecuencia de administración.
2. Comprender qué motiva a los pacientes a cumplir y ser persistentes con el tratamiento, las barreras que impiden el cumplimiento del tratamiento y los tipos de efectos secundarios o limitaciones que están dispuestos a soportar para persistir (o los beneficios esperados que exigirían para persistir). 3. Describir las experiencias de los pacientes con la toma de decisiones sanitarias compartidas.
Diseño del estudio: Este estudio constará de tres fases (véase la figura 2 Protocolo p.26/53). La fase 1 comprenderá una revisión bibliográfica selectiva de las principales características de tratamiento y niveles del EED, y un conjunto de entrevistas cualitativas con 40 pacientes de la UE5 (8 por país). La fase 2 comprenderá la elaboración de una encuesta basada en los resultados de la fase 1, seguida de aportaciones de los principales líderes científicos y entrevistas cognitivas con 40 pacientes de la UE5 (8 por país). A partir de los resultados de esas entrevistas, se ultimará la encuesta. La fase 3 que comprende la recopilación de datos cuantitativos, el análisis y la elaboración de informes con la participación de un máximo de 500 pacientes de la UE5 (100 por país).
La población del estudio estará compuesta por dos grupos:
1. En riesgo de ECVA
2. ECVA establecida
Periodo de estudio: Enero 2024-Marzo 2025
Se llevarán a cabo una encuesta (EDD) sobre la preferencia de las medicaciones: preguntas sobre compensaciones y preferencias de medicación para la ECVA.
Las características de los pacientes se presentarán de forma descriptiva. El análisis de los datos de la encuesta permitirá estimar las ponderaciones de las preferencias para cada nivel de característica incluido en la encuesta EDD mediante un modelo jerárgico bayesiano. Si el tamaño de la muestra lo permite, puede realizarse comparaciones bivariantes para examinar las diferencias de preferencia sin ajustar. Para determinar si las estimaciones de importancia relativa difieren significativamente entre sí por grupos, se utilizarán pruebas paramétricas tradicionales de t para muestra independientes o pruebas de análisis unidireccional de varianza (ANOVA).
Tamaño de la muestra: Se realizará inicialmente entrevistas cualitativas en cada país a 8 pacientes y entrevistas cognitivas para poner a prueba la encuesta a otros 8 pacientes. Posteriormente se realizará la encuesta EDD a 500 personas, 100 por país.
Limitaciones: Los datos serán reportados por los pacientes con lo que conlleva posibles sesgos. El estudio se basará en métodos de muestreo de conveniencia por todo el país, por lo que, a pesar de que se harán esfuerzos en la selección para tener una muestra representative de la población de interés, es posible que ciertos tipos de participantes estén sobrerrepresentados y que los resultados no se puedan generalizar a toda la población.

Antecedentes: La diarrea aguda es extremadamente frecuente tanto en niños como en adultos, con más de seis mil millones de casos cada año en todo el mundo. La mayoría de estos episodios son breves y no dan lugar a una consulta médica pero entre un 1- 10% puede evolucionar a una diarrea persistente o crónica. De hecho, estimaciones recientes indican que, la posibilidad de desarrollar un síndrome de intestino irritable con diarrea varía entre el 4,4% para las infecciones víricas, el 12,9% para las bacterianas y hasta el 53% para las parasitarias. El tratamiento recomendado consiste en la rehidratación oral. Los antibióticos, los inhibidores de la motilidad o las sustancias que disminuyen la secreción de agua y electrolitos pueden ser útiles, aunque con algunos efectos adversos. En la actualidad, existe una sólida justificación para el uso de «mucoprotectores», en el tratamiento de los trastornos diarreicos. Los mucoprotectores comparten la capacidad de crear una barrera formadora de película sobre la mucosa intestinal, ayudando a reducir el efecto de los patógenos y a mejorar la función de la barrera intestinal. Basándonos en todas las pruebas mencionadas, y teniendo en cuenta las propiedades beneficiosas de las diferentes combinaciones de xiloglucano para el tratamiento de la diarrea y su seguridad, queremos comprobar si la combinación de xiloglucano más gelosa es eficaz y segura para el tratamiento de la diarrea aguda en adultos. Hipótesis: La combinación de xiloglucano más gelosa es más eficaz que el placebo para el tratamiento de episodios de diarrea aguda en adultos. Objetivos: evaluar el efecto del xiloglucano más gelosa en la reducción de la duración de la diarrea aguda en adultos, en la reducción de los síntomas asociados, así como su seguridad y tolerabilidad. Métodos: ensayo aleatorizado, multicéntrico, doble ciego, controlado con placebo, en pacientes con diarrea aguda atendidos en la consulta externa de gastroenterología del hospital Vall d’Hebron y en de los varios centros de atención primaria asociados. Se realizará una historia clínica completa, un examen físico y se recogerán, mediante cuestionarios clínicos estructurados, los síntomas digestivos. Los pacientes recibirán Xilaplus AF o placebo a partir del día de la aleatorización y durante cinco días consecutivos. A los 5 días se recogerán de nuevo mediante cuestionarios clínicos estructurados, los síntomas digestivos. Relevancia: Este proyecto, podría generar importantes beneficios para la sociedad en el tratamiento de la diarrea aguda. Además, creemos que el impacto bibliográfico será muy elevado y por ello esperamos obtener publicaciones en revistas como Gastroenterology y Gut (primer decil de nuestra especialidad). Asimismo, los resultados generados por este proyecto serán presentados en congresos nacionales e internacionales de Gastroenterología para facilitar su difusión y futuras colaboraciones con otros grupos de investigación.

Antecedents. L’elevada prevalença de dolor crònic no oncològic (DCNO) i l’augment de la prescripció d’opioides a llarg termini s’associa a reaccions adverses i iatrogènia farmacològica.
Hipòtesi.
• El patró d’us d’opioides en atenció primària està insuficientment descrit.
• Hi ha pràctiques insegures i de poc valor en el maneig del DCNO.
• Es detectaran diferències en relació amb el gènere (sobreutilització i sobredosificació).

Objectius.
General: Descriure l’ús dels opioides amb perspectiva de gènere i identificar usos inadequats per proposar millores d’ús.
Específics
• Descriure les característiques dels pacients segons els patrons d’ús i la dosis prescrita tenint en compte el gènere.
• En DCNO, identificar situacions de risc segons les dosis equivalents de morfina (DEM): a partir dels 50 mg/dia; a partir de 90 mg/dia; i quan es recomani ajust de dosi (malaltia renal crònica, hepàtica i tractaments concomitants).

Metodologia
Disseny: Estudi de cohorts retrospectiu que analitzarà 3 bases de dades pseudonimitzades europees (SIDIAP-Catalunya, Clinical Practice Research Datalink -UK, Integrated primary Care Information-Països Baixos).
Període d’estudi: D’1 de gener 2022 a 31 de desembre de 2024.
Les dades es maparan al model comú de dades Observational Medical Outcomes Partnership.
Àmbit i població: Adults (=18 anys) amb tractaments amb opioides.
Variables d’estudi: Demogràfiques (edat, gènere, centre, institucionalització), problemes de salut, comorbiditat, filtrat glomerular, tractament farmacològic, efectes adversos i interaccions rellevants.
Anàlisi estadística: Descriptiva, T de Student, Chi-quadrat, regressió logística. Programa R.
Resultats esperats: S’espera identificar usos inadequats.
Aplicabilitat i rellevància: Proposar millores en la pràctica clínica per augmentar la seguretat i l’efectivitat en l’ús d’opioides.

– Antecedents: La iintel·ligència artificial (IA) por ajudar a la monitorització i control dels pacients amb malalties cròniques com els que tenen diabetis o hipertensió. L’eina ISAC es un chatbot amb IA que vol ser d’ajut al assistent clínic per fer aquestes tasques.
– Objectiu: Dissenyar, validar i avaluar l’eficàcia d’una eina basada en AI-G (ISAC), que donarà suport al assistent clínic, en el maneig del pacients diabètics, hipertensos i en el cribratge d’hàbits de vida (consum de tabac, alcohol i exercici físic) en la població adulta general a l’àmbit de l’atenció primària.
– Metodologia: Es portaran a terme dos sub-estudis:
1. Disseny i validació de l`ISAC amb una base de dades d’atenció primària (MAPAMED) prèviament pseudo-anonimitzada, del 01/01/2022 al 31/12/2023. Es farà un estudi de cohorts restrospectiva. El objectiu d’aquesta validació es valorar si l’eina ISAC es capaç de detectar la informació mancant, necessària per una correcta monitorització dels malalts, a les histories clíniques dels pacients inclosos en 3 cohorts: amb diabetis, amb hipertensió o en una cohort de població general. S’exclouran tots els pacients amb institucionalitzats, pacients MACA (esperança de vida <1 any), pacients amb malalties neoplàsiques terminals, pacients que s’hagin donat de baixa al centre durant el període d’estudi y pacients no visitats durant el període d’estudi. L’eina identificarà la següent informació mancant: sociodemogràfica, de estils de vida (tabac, alcohol, exercici físic), dades de laboratori, derivacions a especialistes, visites a infermeria i altres professionals sanitaris. Els llistats amb les variables mancants seran validats per cada un dels professionals de referencia dels pacients per tant de validar si efectivament aquesta informació està mancant o o no. S’ha estimat que fa falta 336 pacients en total per aquest estudi (112 per cohort). Es realitzarà un anàlisi descriptiu de totes les variables i es calcularà el valor predictiu positiu i negatiu 2. Estudi quasi experimental amb grup control en un centre d’atenció primària per a comparar l’eficàcia de l’eina ISAC en la monitorització de pacients diabètics, hipertensos, en el cribratge d’hàbits de vida en la població adulta general i en la reducció de visites de medicina i d’infermeria. A més, aquest assaig avaluarà l’acceptabilitat, experiència d'ús i satisfacció dels assistents clínics i dels pacients amb l’eina. - Determinacions: Dades sociodemogràfiques (edat i sexe), de laboratori, derivacions, proves complementaries, diagnòstics. - Anàlisi estadística: es farà un anàlisis estadística descriptiva. Es calcularà el valor predictiu positiu i negatiu.

Antecedentes: La intolerancia a la lactosa constituye un motivo frecuente de consulta en atención primaria, donde la inespecificidad de los síntomas dificulta el diagnóstico diferencial y puede llevar a pruebas innecesarias. El LacTEST 0,45 g, utilizado ampliamente en España, ofrece una alternativa diagnóstica segura para identificar hipolactasia mediante la determinación de xilosa en orina. Sin embargo, su impacto real en el manejo clínico y en la evolución de los pacientes dentro del ámbito comunitario aún no se ha evaluado de forma sistemática. El presente estudio busca valorar su utilidad diagnóstica y clínica en pacientes atendidos en el centro EAP Sardenya.
Hipótesis: La prueba diagnostica LacTEST en atención primaria permite identificar mejor los pacientes con una intolerància a la lactosa y mejora el manejo (clínico y de costes) de estos pacientes.
Objetivos: El objetivo principal es evaluar el impacto clínico del LacTEST 0,45 g en pacientes con síntomas sugestivos de intolerancia a la lactosa. Entre los objetivos específicos se incluyen clasificar a los pacientes según los resultados del test, valorar la evolución de la sintomatología y de la calidad de vida tras la intervención dietética, analizar la seguridad del procedimiento y estudiar su efecto en el uso de recursos sanitarios.
Metodología: Para alcanzar estos objetivos se llevará a cabo un estudio observacional que constará de dos fases.
Fase 1: estudio observacional prospectivo en pacientes de 16 años o más del centro EAP Sardenya durante 2026. Los médicos de familia identificarán a los pacientes con síntomas compatibles con intolerancia a la lactosa candidatos a realizar el LacTEST según práctica clínica habitual. Tras confirmar los criterios de inclusión y obtener el consentimiento informado, se realizará una visita basal donde se recogerán datos clínicos, sociodemográficos y de calidad de vida. Los participantes realizarán en su domicilio el LacTEST 0,45 g siguiendo el protocolo establecido, y las muestras se analizarán mediante determinación enzimática de xilosa en orina en el laboratorio de referencia. En la visita posterior se comunicarán los resultados y, según el nivel de xilosa, los pacientes se clasificarán como normolactásicos o hipolactásicos. En estos últimos se indicará la retirada personalizada de lácteos durante dos meses. En una tercera visita se reevaluarán los síntomas y la calidad de vida, pudiendo repetirse el test para confirmar el diagnóstico. En caso de no mejoría, se hará un diagnóstico diferencial con otras patologías digestivas. El tamaño muestral estimado para el estudio observacional prospectivo es de 395 pacientes.
Fase 2: Para el estudio de coste-eficiencia, se llevará a cabo un estudio observacional retrospectivo en todos los pacientes con un diagnóstico de intolerancia a la lactosa en los que se haya retirado la lactosa de la dieta entre los años 2002 y 2024. Previo consentimiento informado, se les pedirá que completen el cuestionario de calidad de vida (EQ-5D-5L) y se registrarán, mediante revisión de su historia clínica, datos sobre visitas, derivaciones a especialistas y pruebas complementarias desde el inicio de los sintomas de intolerancia a la lactosa hasta la confirmación diagnóstica. El tamaño muestral estimado para el estudio observacional retrospectivo es de 93 (la totalidad de pacientes con el diagnóstico registrado).
Analisis estadisticos: En el sub-estudio 1 se realizará un análisis descriptivo de las variables demográficas y clínicas, resumiendo las cuantitativas mediante media, desviación estándar, mediana y rango, y las cualitativas mediante frecuencias y porcentajes. Se estimará la proporción de pacientes con normolactasia o hipolactasia según LacTEST 0,45 g y las acciones clínicas derivadas. En los sujetos hipolactásicos se repetirá el test a los 2 meses de la dieta sin lactosa. Las comparaciones por sexo, edad y síntomas se efectuarán mediante pruebas Ji-cuadrado o t de Student según corresponda. La evolución clínica en pacientes hipolactásicos se evaluará comparando puntuaciones VAS y EuroQol mediante t de Student apareada. Los participantes podrán retirarse del estudio, excluyéndose sus datos de análisis posteriores.
En el sub-estudio 2 se llevará a cabo un análisis de coste-efectividad mediante el cálculo del ICER anual para comparar la realización frente a la no realización del test de xilosa, incorporando costes diagnósticos, asistenciales y laborales. A partir del cuestionario EQ-5D-5L se obtendrán valores de utilidad para el cálculo de QALYs y la estimación final de la eficiencia de cada estrategia.
Aplicabilidad y relevancia: La evaluación del LacTEST permitirá valorar su impacto en la practica clinica habitual de atención primaria, como por ejemplo la reducción en las derivaciones innecesarias y la redución de pruebas complementarias. Los resultados de este estudio podran fortalecer la evidencia sobre la utilidad del LacTEST en el contexto real de la atención primaria

Antecedents: La gota afecta un 2,5% de la població de més de 15 anys al nostre entorn (1). La seva incidència està augmentant degut bàsicament a l’envelliment de la població i els canvis en l’estil de vida en tot el món desenvolupat (2). La manifestació clínica més característica és la pruaga, però si no es tracta els episodis d’artritis són poliarticulars i apareixen els tofus i la destrucció articular. A més, avui dia, no tenim dubte que la gota s’associa a un augment de risc cardiovascular, empitjorament de la funció renal i augment de la mortalitat (3,4). Malgrat tenir una rellevància creixent i tenir un tractament conegut i efectiu, és una malaltia infratractada (5,6). Hi ha poques dades epidemiològiques o de característiques clíniques de malalts gotosos en el nostre entorn i a l’atenció primària.
– Objectiu: Avaluar l’ús dels tractaments hipouricemiants en els pacients amb gota a l’atenció primària de Catalunya i descriure les seves característiques clíniques i sociodemogràfiques.
– Metodologia: Estudi observacional longitudinal de cohorts retrospectives de base poblacional.
– Determinacions: Edat, sexe i índex socioeconòmic. Anys d’evolució de la malaltia, nivells d’uricèmia, filtrat glomerular i IMC. Comorbiditats: hipertensió, diabetis mellitus tipus 2, dislipèmia, cardiopatia isquèmica, obesitat, malaltia cerebrovascular, malaltia renal crònica. Consum de tabac i alcohol. Tractament hipouricemiant i amb colquicina: principi actiu i dosi, duració del tractament, període d’exposició, adherència al tractament hipouricemiant. Altres tractaments. Mortalitat.
– Anàlisi estadística: Les característiques de la població es descriuran mitjançant una anàlisi descriptiva. Es calcularà mitja, mediana, valor màxim i mínim i desviació estàndard per a variables contínues i freqüència absoluta i relativa per a variables categòriques. Per a comparar proporcions s’utilitzarà la ?2 i per a mitjanes la prova T de Student. S’estudiarà la prevalença i incidència acumulada del grau de control de la malaltia, mortalitat i tractament reductor de la uricèmia. S’utilitzarà el mètode Kaplan-Meier per a calcular la persistència al tractament hipouricemiant. Tots els resultats seran estratificats per edat, sexe i estatus socioeconòmic.
– Resultats esperats, aplicabilitat i rellevància: S’espera que els pacients amb gota estaran infratractats, amb comorbiditat i mortalitat altes. Aquests resultats ens ajudaran a identificar punts de millora i seran aplicables a l’atenció primària del nostre país. Serà la primera cohort de malalts gotosos de Catalunya.

Existe controversia con respecto al uso de la vitamina D y el riesgo de fracturas osteoporóticas. Actualmente el 80% de los suplementos de vitamina D está prescritos a personas con bajo riesgo de fractura o sin déficit de vitamina D por lo que es necesario identificar la población que se beneficiarían más de estos los suplementos en relación al riesgo de fracturas osteoporóticas.

Objetivos: Determinar la incidencia anual por cada 100.000 personas-año de las fracturas osteoporóticas. Determinar la asociación entre los niveles de vitamina D en sangre, el uso de suplementos con vitamina D y las fracturas osteoporóticas en
1.Sujetos mayores de 45 años, 2. Sujetos con osteoporosis y en 3. Sujetos con tratamiento para la osteoporosis (bifosfonatos, denosumab, teriparatida, moduladores selectivos de la recaptación de estrógenos)

Metodología:
1. Estudio de cohortes para el análisis de la incidencia de fracturas osteoporóticas
2. Estudio de casos-control anidado para analizar la asociación entre las fracturas osteoporóticas, los niveles de vitamina D en sangre y la dispensación de vitamina D. Los casos serán aquellos con una primera fractura osteoporótica, emparejados con hasta 5 controles/caso por edad, sexo, índice de masa corporal e índice de deprivación socioeconómica. Los datos se extraerán de la base de datos SIDIAP (Sistema de Información para el Desarrollo de la Investigación en Atención Primaria y de las altas hospitalarias de la base de datos CMBD (Conjunto Mínimo Básico de Datos). Periodo estudio: 2007-2023. Variables de Exposición: niveles de vitamina D en sangre (25(OH)D) y dispensaciones de vitamina D (con o sin calcio). Variables de resultado: Fracturas osteoporóticas (todas excepto, cara, cabeza y dedos). Otras variables: sociodemográficas, tabaco, alcohol, valores de densitrometría ósea, función renal, comorbilidades y medicaciones. Análisis estadístico: Incidencia acumuladas por 100.000 personas-año. modelos de regresión logística (95% IC).

– Antecedentes: La gota es la artropatía inflamatoria más prevalente, afecta un 2,4% de la población. Es una enfermedad que predomina en hombres, en proporción 4/1. Quizás por esto, y por la brecha de género que aún hoy día presentan las responsabilidades en la crianza de los hijos, nunca se ha estudiado si el hecho de tener gota tiene un impacto en la crianza de los hijos.
– Objetivos: El objetivo principal del estudio es describir las opiniones y experiencias de las personas con gota sobre el impacto de la gota en la crianza, según género.
– Metodología: Estudio cualitativo de diseño exploratorio y metodología fenomenológica, mediante entrevistas semiestructuradas cara a cara y/o con videollamada.
– Determinaciones: Se reclutaran los participantes necesarios para garantizar la heterogeneidad y la variedad de discursiva. Se recogerán:
– Características demográficas y de la enfermedad.
– Experiencias del paciente con gota y crianza. Afectación de capacidades físicas, emocionales, educativas, de socialización y económicas.
– Afectación en la realización de actividades del hogar y existencia de apoyo en su entorno inmediato.
– Otras experiencias: autocuidado, comunicación con médicos habituales e impacto en otros aspectos de la vida.
– Análisis estadístico: temático reflexivo, de transcripciones literales de las entrevistes que permita identificar temas y categorias, para realizar un análisis analítico inductivo.
– Resultados esperados, aplicabilidad y relevancia: Conocer las experiencias y percepciones de las persones con gota respecto a la crianza podrá ayudarnos a entenderlos y a buscar maneras para que estos afronten con más garantía de éxito las dificultades que su enfermedad les provoca

Objetivos: Analizar la asociación entre las medicaciones potencialmente inadecuadas (MPI) de la herramienta STOPPFall (Screening Tool of Older Persons Prescriptions in older adults with high fall risk) y los eventos adversos (hospitalizaciones, mortalidad general, caídas, fracturas y demencia) en atención primaria.
Material y métodos: Estudio de cohortes retrospectivo y de casos-control anidado del 2010 al 2024 usando datos anonimizados de la base de datos SIDIAP (www.sidiap.org) que recoge información médica de atención primaria de >5.8 millones de sujetos (75% de los centros de salud de Cataluña). Los = 65 años, con = 365 días de seguimiento previo y sin ninguno de los eventos adversos a estudio, serán incluidos en las cohortes de 1. Expuestos a MPI (=1 dispensación durante el periodo de estudio) o 2. No expuestos a MPI (en ningún momento dado). Para los estudios casos-control, los casos serán aquellos con un primer evento adverso (hospitalización, mortalidad general, caídas, fracturas o demencia) durante el periodo de estudio. Se emparejarán con controles mediante el procedimiento “optmatch”, por edad, sexo, índice de comorbilidad de Charlson (ICC) y número de medicaciones (excepto MPI). Seguimiento: desde su entrada en la cohorte, inicio del estudio o primera dispensación de MPI (cohorte de expuestos), hasta el evento adverso, fin del estudio, traslado a otro centro o 1 año de seguimiento.Variables de exposición: MPI del listado STOPPFall (benzodiacepinas e hipnóticos, antipsicóticos, opioides, antidepresivos, anticolinérgicos, antiepilépticos, diuréticos, bloqueadores alfa, antihipertensivos centrales, antihistamínicos, vasodilatadores usados en enfermedad cardiaca, medicaciones para la incontinencia urinaria). Variables de resultado: primer registro de hospitalización, mortalidad general, caída, fractura o demencia. Otras variables: datos sociodemográficos, hábitos tóxicos (alcohol y tabaco), índice de masa corporal, número/tipo de MPI, índice de deprivación socioeconómica (MEDEA), visitas en atención primaria (año previo), comorbilidades y medicaciones identificadas como confusoras. Se calculará el porcentaje de exposición a MPI: baja (<25%), media (25-74%) o alta (=75%). Análisis estadístico: Se calculará la incidencia anual total y para cada MPI de los eventos adversos por cada 100 000 personas-año, con intervalo de confianza 95% (IC 95%). Se determinará (regresión logística) el riesgo del evento adverso entre expuestos y no expuestos y en función del porcentaje de exposición a MPI comparado con sujetos con una exposición baja (<25%) (referencia). Las ODDs Ratio, con IC 95%, se ajustarán por edad, sexo, estatus socioeconómico y factores confusores. Los resultados se estratificarán por edad, sexo y estatus socioeconómico. La significación estadística se establecerá en p-valor<0,05. El análisis estadístico se realizará con el programa STATA MP/18 (StataCorp, Texas, USA) y el programa R 4.3.3. Aplicabilidad de los resultados esperados: Los resultados permitirán caracterizar e identificar la población con más riesgo de sufrir eventos adversos debidos a la MPI y determinará si existen diferencias por género en la incidencia de estos eventos adversos.

The risk of experiencing Adverse Drug Reactions (ADR) is inherent in drug therapy initiation and influenced by characteristics of the drug and the patient. ADRs pose a threat to patient safety, leading to increased morbidity and mortality, and contribute to decreased adherence to treatment regimens. ADR-associated costs for healthcare systems sum up to $30.1 billion in the US and €79 billion in Europe. Although primary care clinicians are responsible for the monitoring and harmonizing of prescription drugs, most ADR research has been carried out in hospital settings. Artificial Intelligence (AI) techniques (machine learning and deep learning) have been used in pharmacovigilance in the analysis of free-text from ADR reports issued by patients and clinicians, yet its application in primary care settings is still to be explored. In Spain, prescription drugs have a summary of product characteristics which details the ADR reported in randomized controlled trials and post-authorization studies. However, their review is time-consuming, as it needs to be done manually, and not always possible during routine visits, where limited resources and time constraints affect the family physician practices. Furthermore, the increased polypharmacy of the population hampers the rapid detection of ADRs, putting patients’ safety at stake. The Real-time Adverse Drug Reaction Automated Recognition tool (RADAR) aims to use AI methods to compile the information of ADRs and combine it with the patients’ clinical information to assess the risk of ADRs for each of the new diagnoses registered. The RADAR tool will also provide first-hand real-world data on ADR the incidence, characteristics and type of ADR in primary care. When implemented in electronic medical records in primary care and used by healthcare professionals during routine clinical visits, the RADAR tool has the potential to speed up and enhance the detection of ADRs, improving patient safety

Las enfermedades reumáticas inflamatorias (IRMD) incluyendo la artritis reumatoide (AR), el lupus eritematoso sistémico (LES), la artritis psoriásica (APs), la esclerosis sistémica (SSc) y las espondiloartropatías (Spa) entre otras están asociadas con un aumento significativo de la morbilidad y mortalidad. La carga de enfermedad de dichas patologías en nuestro entorno no es bien conocida. Nuestros objetivos son:
1) Evaluar la carga de enfermedad de IRMD en Cataluña, estimando su prevalencia e incidencia,
2) determinar los factores independientes asociados con las complicaciones de las IRMD en comparación a la población sana, incluyendo la enfermedad coronaria, la enfermedad tromboembólica, la diabetes mellitus, las fracturas osteoporóticas, las infecciones graves, el cáncer y la insuficiencia renal crónica y
3) Estimar el impacto de las IRMD sobre la mortalidad en comparación a la población general.
Para ello proponemos un estudio poblacional retrospectivo que incluirá todos los casos identificados mediante códigos ICD-10 del programa del Sistema de Información para el Desarrollo de la Investigación en Atención Primaria (SIDIAP) del 2006 al 2021. El SIDIAP cuenta con información de mas de 5.7 millones de habitantes e incluye datos demográficos, diagnósticos, prescripciones/dispensaciones y fecha de muerte.
Se utilizará una cohorte de control sin IRMD apareada por el año de nacimiento, género, y estado socio-económico como grupo control.

There is a lack of scientific literature on the characteristics of patients who have subsequent osteoporotic fractures and on their associated burden compared to single osteoporotic fractures.

OBJECTIVES:
1. To describe the characteristics of postmenopausal women with an imminent subsequent fracture
2. To describe the incidence of imminent subsequent fractures (fractures within 2 years after an index fracture) amongst postmenopausal women
3. To estimate the impact of an imminent subsequent fracture on healthcare resource utilisation and direct costs amongst postmenopausal women.

Data sources
This study will be done with the SIDIAP-OMOP data (Obervational and Medical Outcome Partnership Common Data Model) as well as in other 5 countries as a Network stuty cohort (UK, Frances, Germany, Italy, The Netherlands). No data extraction is required from SIDIAP just the Data Access to SIDIAP-OMOP. The Health Care Resource Utilization for Objective 3 will be calculated based on the registries of visits (primary care and hospitalizations) and procedures (referals) as well as drug use.

METHODS:
Study design and population: Retrospective cohort study of all women aged =50 years with a require observation time of at least 730 days pre-index date and will be followed-up for a maximum of 730 days.

Study period: 01 April 2008 to 31 March 2020 (included the pre-index and follow-up required observation period)

Exclusion: Patients with <730 days observation time prior to the index date, those with cancer (except non-melanoma skin cancer), Paget's disease of the bone, or other metabolic bone diseases (e.g., osteomalacia, hyperparathyroidism, osteogenesis imperfecta) at any time prior to and including index date will also be excluded. Three cohorts are of interest: (1) Patients with an index fracture and at least one previous fracture (of any type except facial, skull or digit fracture) in the prior two years, making the index fracture the imminent subsequent fracture (2) comparator cohort 1 includes patients with an index fracture and no history of fracture in the two years prior (3) comparator cohort 2 includes patients with no history of fracture at any time. Follow-up: from the index date until the first date of occurrence of the censoring events: cancer (except non-melanoma skin cancer); Paget's disease of the bone; or other metabolic bone diseases; 730 days after index date; death; end of data collection period; ensuing fracture after the imminent subsequent fracture in the target cohort; ensuing fracture after the index fracture in the comparator cohort 1; or incident fracture in the comparator cohort 2. For the first and second objectives, comparator cohort 1 is of interest. The date of the index fracture for this cohort will be the index date. For the third objective, the healthcare resource utilisation and direct costs amongst (i) patients in cohort 1(target cohort) will be compared with patients with in the comparator cohort 1 and, (ii) patients in the comparator cohort 1 will be compared with patients in the comparator cohort 2. Age and propensity score matching will be performed on an iterative, rolling basis over calendar time. The propensity score will be constructed on the index date. For the target cohort, the index date will be the date of imminent subsequent fracture. For the comparator cohort 1, the index date will be the date of fracture. For the comparator cohort 2, the index date will be a random date chosen in the specific 6-month period as long as the patient is alive at that date. VARIABLES: Demographics (Age), Charlso Comorbidity Index, Comorbid conditions (Fractures, Cardiovascular disease, DM, Chronic Kidney disease, Hiperlipidemia, Vitamin D deficiency, hypocalcemia, hypothyroidism, hypoparathyroidism), laboratory measurements, procedures, and medications (exposures to medications that incluence the risk of fracture) as well as number of GP and hospital contacts and drugs prescribed. We will define baseline covariates according to three time-windows prior to the index date: any time, 720 days and 180 days. OUTCOMES: 1-Imminent subsequent fracture occurring within two years of the previous fracture (objective 2), 2-Healthcare resource utilisation and direct costs measured from the index date until the end of follow-up (objective 3). DATA ANALISIS For Objective 1: the baseline patient characteristics of comparator cohort 1 will be described. For Objective 2: the incidence rate for an imminent subsequent fracture amongst postmenopausal women with an index fracture will be calculated (i.e within comparator cohort 1). Next, the cumulative incidence of imminent subsequent fractures will be calculated using the Fine and Gray model whilst accounting for the competing risk of death. Results will be stratified by the number of times the patient has entered the cohort. For Objective 3: large scale L1 regularised regression will be used to identify confounders and covariates predictive of outcome from a large set of candidate covariates. The propensity score, the probability of exposure assignment conditional on observed baseline patient characteristics, will be estimated using logistic regression including covariates identified from L1 regularized regression. Age- and propensity score matching would then be performed. Baseline patient characteristics and absolute standardised mean differences will be described before and matching for the two comparisons (target cohort vs. comparator cohort 1, comparator cohort 1 vs. comparator cohort 2). The expected incremental healthcare resource utilisation and direct costs amongst (i) patients with an imminent subsequent fracture (target cohort) compared with patients with a single fracture (comparator cohort 1) and, (ii) patients with first fracture (comparator cohort 1) compared with patients with no fracture (comparator cohort 2) will be estimated using generalised linear models. These comparisons are made as our hypothesis is that added burden due to subsequent imminent fracture increases exponentially rather than linearly.

This project is part of Andrea Pistillo’s PhD thesis project. A part of the project has received funds from Ajuntament de Barcelona «Subvencions extraordinàries per a projectes de recerca i innovació en col·laboració amb la Fundació La Caixa, 2022». We lead the project from IDIAPJGol and other two institution are partners: ISGlobal and ICTA-BCNUEJ.

Environmental exposures may affect people’s lives. In particular heatwaves and peaks in air pollution had been associated with more mortality and hospitalizations, and a worst life quality. In Barcelona and its metropolitan area, these two types of exposures affect the neighbourhoods in a different way, both for geographic reasons (neighbourhoods nearer to the sea had a milder temperature during daytime) and sociodemographics ones (older population, energy poverty, areas with less green spaces, low education). Higher temperature and air pollution had been linked to respiratory, cardiovascular, mental, perinatal problems and infectious diseases. So far, this problems had been studied in hospital settings and a comprehensive study in primary care is needed to understand both the prevalence of the problems due to these environmental exposures and the burden of this on the primary care system. In this project we aim to analyze the relationship among temperature and air pollution on the health of the citizens of Barcelona and its metropolitan area. We will perform a quantitative study using the newest methodologies (case time series), and we will link daily environmental exposures with three types of health indicators (diagnosis, medications registered in primary care and sick leaves). The focus will be on neighborhoods and will take into account gender perspective and multidisciplinarity, justified with the synergy of the three institutions involved. An important part of the project will be dissemination of results, indeed we will publicly publish a risk map with the results in which citizens and policy makers will be able to interactively visualize the results of the project (at a neighborhood scale).

«Background
The current COVID-19 vaccines include mRNA vaccines, non-replicating viral vector vaccines and traditional inactivated whole virus vaccines. All of them have demonstrated their effectiveness against confirmed COVID-19 infection in previous and ongoing clinical trials However, vulnerable populations, such as pregnant women, children, individuals living in nursing homes, those with cancer, autoimmune diseases, immunodeficiencies or organ transplant recipients were systematically excluded from these trials, limiting the available evidence regarding the efficacy of the COVID-19 vaccines on these patients to retrospective observational studies, and small non-randomized trials with surrogate endpoints (e.g. antibody levels).

Objectives
To estimate coverage and the effectiveness of COVID-19 vaccines against COVID-19-related outcomes in vulnerable populations, overall and by sex, age, baseline comorbidities, and socioeconomic status, using electronic health records from Catalonia, Spain.
1- To provide periodic estimates of vaccine coverage in predefined subgroups of population at risk of being excluded from the general vaccine campaigns (i.e individuals with mental disorder), stratified by vaccine type/brand, vaccine dose, sex, age groups, socioeconomic status, and nationality.
2- To assess the effectiveness of COVID-19 vaccines in vulnerable population against COVID-19 related outcomes (COVID-19 infection, hospitalisation, intensive care admission, or death) in:
2.1- pregnant women and infants up to 12 months of age;
2.2- children and adolescents from the age of 5 to 19 years;
2.3- persons living with immunodeficient conditions, namely cancer, autoimmune conditions, primary immunodeficiencies, people living with HIV infection, organ transplant recipients or people taking immunosuppressive drugs;
2.4- persons living in nursing homes.

Methods
We will conduct a population-based matched cohort study using individual-level routinely-collected electronic health records (EHR) data from the Information System for Research in Primary Care (SIDIAP; www.sidiap.org) database in Catalonia mapped to the OMOP-CDM.

Study population
We will include all women with a pregnancy episode during the study period (mother-child linkage), children and adolescents, as well as those with history of cancer, immunodeficient conditions (HIV, autoimmune diseases, organ transplant recipients) and/or use of immunosuppressive drugs (including high chronic use of corticosteroids, biological and non-biological disease modifying drugs, antineoplastic drugs), persons living in nurse home residencies or persons with mental health conditions of any age, registered for at least 365 days in the SIDIAP database prior to the 27th of December 2020 (date of initiation of the vaccination in Spain) and up to December 2022 and December 2023.

Exposures
Four COVID-19 vaccines will be included: ChAdOx1-S, BNT162b2, mRNA-1273, and Ad26.COV2.S.

Outcomes
The main outcomes to evaluate effectiveness of COVID-19 vaccination will include: 1.SARS-CoV-2 infection will be defined as any confirmed infection identified by diagnostic codes and/or a positive RT-PCR or antigen test result, 2.COVID-19-related hospitalisation will be defined as a hospital admission (at least one night) where the individual had a positive RT-PCR test result or a clinical diagnosis of COVID-19 over the 21 days prior to their admission up to the end of their hospital stay,3. COVID-19-related intensive care unit (ICU) admission in those with COVID-19 related hospitalisation, 4.COVID-19-related death will be defined as death (any cause) registered after a COVID-19-related hospitalisation or 28 days after a SARS-CoV-2 infection.

Covariates
Covariates to be considered in the analyses will include demographics, socioeconomic status, nationality and diagnosis of mental health condition (only for coverage), BMI, pre-existing comorbid conditions, history of COVID-19 infection (6 months previous), period of predominant SARS-CoV-2 variants, number of GP visits per year, pregnancy variables (gestational age at vaccination, parity, breastfeeding, maternal lifestyle behaviour factors (when available).

Follow-up
For individuals from the age of 5 and above follow up will be from their index date to occurrence of an event, end of pregnancy (for pregnancy cohort), death, or loss of visibility in the database (e.g., person leaving the practice in electronic health records data). For cohorts that had received a first vaccine dose, we also censored follow-up if a second dose was observed before 21 days for BNT162b2 and before 27 days for mRNA-1273 and ChAdOx1-S.
The index date for exposed children (up to 12 months of age) will be the date of maternal vaccination. Children will be followed from the index date until occurrence of an event of interest, exit from the database, death, end of pre-defined follow-up time (12 months after birth), or end of data availability, whichever comes first.

Statistical analysis
Vaccination uptake rate will be calculated as the number of persons receiving any COVID-19 vaccines in a certain population subgroup divided by all individuals eligible for vaccination in that group.
We will conduct a new user cohort study, to compare the effectiveness of COVID-19 vaccines against COVID-19-related outcomes. We will use propensity score (PS) matching to minimise the risk of confounding. Vaccinated individuals will be matched in a 1:3 ratio (if sample size allows) with eligible non-vaccinated individuals with no prior history of COVID-19 infection in the past 3 months. Matching will be done taking into account age group, sex, calendar time, baseline comorbidities associated with increased risks of severe COVID-19 (e.g., obesity, diabetes, immunosuppression), and smoking. We will also use a large-scale, data-driven approach to identify additional potential confounders to be included in the PS.

Ranitidine is a competitive and reversible inhibitor of the action of histamine and indicated for the management of peptic ulceration (with or without Helicobacter Pylori), Gastro-Esophageal Reflux Disease (GERD), reflux oesophagitis and Zollinger-Ellison syndrome. In 2019, results of a preliminary laboratory analysis have shown the presence of NNitrosodimethylamine (NDMA), a human carcinogen, in ranitidine.
The European Commission triggered on 12 September 2019 a referral procedure to evaluate the relevance of these findings, the potential root causes and their impact on the benefit-risk balance of medicinal products containing ranitidine. Based on this evaluation, in April 2020 EMA’s Committee for Medicinal Products for Human Use (CHMP) has recommended the suspension of all ranitidine-containing medicines in the
EU due to the presence of low levels of NDMA impurities.
Many ranitidine-containing medicines have not been available in the EU for several months since the initiation of the referral, because national competent authorities have recalled them either due to levels of NDMA found in the products or as a precaution while the EMA review is ongoing. Healthcare professionals have been asked to advise patients on alternative medicines. In addition, in some Member States the outcome of the referral was communicated at national level through media campaigns,
involving learned societies and medical associations to inform prescribing physicians and health care organisations about these changes.
The unavailability of ranitidine-containing medicines is expected to cause patients to switch treatment to alternative medicines or alternative treatment strategies. The extent of switches to alternative medicines remains unknown as well as the rate of patients permanently discontinuing treatment following unavailability of ranitidine-containing medicines.

The overall aim of this study is to evaluate the impact of the regulatory actions taken for ranitidine containing medicinal products following the 2019 referral procedure, using healthcare databases of six European countries.

Background and Significance: Type 2 diabetes mellitus (T2DM) is a major cause of morbidity and mortality globally and is associated with an elevated risk of cardiovascular events. Therapeutic options for T2DM have expanded over the last decade with the emergence of sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP1) receptor agonists, which reduced the risk of major cardiovascular events in randomized controlled trials (RCTs). Cardiovascular evidence for older second-line agents, such as sulfonylureas, and direct head-to-head comparisons, including with dipeptidyl peptidase 4 (DPP4) inhibitors, are lacking, leaving a critical gap in our understanding of the relative effects of T2DM agents on cardiovascular risk and on patient-centered safety outcomes.

Study Aims: To determine real-world comparative effectiveness and safety of traditionally second-line T2DM agents using health information encompassing millions of patients with T2DM, with a focus on individuals at moderate cardiovascular risk and other key subgroups.
Study Description: We will conduct three large-scale, systematic, observational studies to make pairwise comparisons of all SGLT2 inhibitor, GLP1 receptor agonist, DPP4 inhibitor and sulfonylurea agents at the drug-, class- and population subgroup-level within our proposed Large-Scale Evidence Generations Across a Network of Databases for T2DM (LEGEND-T2DM) initiative. LEGEND-T2DM will leverage the ObservationalHealth Data Science and Informatics (OHDSI) community that provides access to a standing global network of administrative claims and electronic health record (EHR) data sources. The 13 data sources already committed to LEGEND-T2DM cover > 190 million patients in the US and about 50 million internationally, and include two academic medical centers, IBM MarketScan and Optum databases, and the US Department of Veterans Affairs. LEGEND-T2DM will study invite other OHDSI data custodians around the world to participate in the study.

Population: Adult, T2DM patients who newly initiate a traditionally second-line T2DM agent, including individuals with and without established cardiovascular disease.

Our systematic framework will address residual confounding, publication bias and ?-hacking using data-driven, large-scale propensity adjustment for measured confounding, a large set of negative control outcome experiments to address unmeasured and systematic bias, prespecification and full disclosure of hypotheses tested and their results. These approaches capitalize on mature OHDSI open source resources and a large body of clinical and quantitative research that the LEGEND-T2DM investigators originated and continue to drive. Finally, LEGEND-T2DM is dedicated to open science and transparency and will publicly share all our analytic code from reproducible cohort definitions through turn-key software, enabling other research groups to leverage our methods, data, and results in order to verify and extend our findings.

Serious adverse events have been reported among antidementia drug users. We aim to analyse the use and comparative safety of the antidementia drugs in primary care centres in Catalonia (Spain).
Design: A population-based cohort study using real-world primary health care data (SIDIAP database), standardized to the Common Data Model OMOP with hospital linkage (CMBD database). A nested case-control approach will be adopted to assess risk of adverse events (AE) during the study period (2007-2020). Inclusion criteria: for the drug utilization study (DUS) we will include individuals with at least 40 year or older with dementia, registered for at least 1 year before cohort entry and with at least 1 prescription of rivastigmine, galantamine, donepezil or memantine during study period. For the safety study we will include patients from the DUS with an incident use (no previous 365 days use) of any of the study drugs. For the nested case control analysis, we will create a cohort of patients with dementia without treatment (anytime). Exposure (DUS/Safety): prescription of rivastigmine, donepezil, galantamine or memantine. Outcomes: (DUS) demographics, comorbidities, prescriber-type, prescribing pattern and proportion of ‘prescription cascade’ drugs (prescriptions generated to alleviate adverse events). Outcomes (safety study): AEs related to disorders of the skin, cardiovascular, gastrointestinal, neurological, psychiatric, sleep, urinary and respiratory disorders, falls, hospitalizations and all-cause mortality.
Statistics: Yearly age-sex incidence rates (IR) and Kaplan Meier curves to assess the duration and drug discontinuation. Adjusted and unadjusted IR of AEs, Hazard Ratios (95% confidence intervals (CI)) using Cox proportional hazard models, and Odds Ratios (95% CI) using nested case-control analysis with conditional logistic regression will be assessed. Each case will be matched (age, sex, Charlson Comorbidity Index and socioeconomic status) with up to 10 controls.
Expected results: With this large population-based cohort study based on routinely collected primary care data with hospital linkage we expect to provide an in-depth characterization of the population that uses any of the currently commercialised antidementia drugs. Because we are using routinely collected real-world information, which differs from the information gathered in randomized controlled trials, we will be able to provide a more accurate picture of the patients that finally receive the drugs to treat dementia. We will also analyse the proportion of patients with a ‘prescription cascade’ and this will contribute to the identification of adverse events that have been misclassified as new medical conditions. Finally, the comparative safety study carried out will inform us about the risk of adverse events between users and non-users of antidementia drugs. Given the increasing availability of non-pharmacological treatments to treat dementia, this information will help clinicians to assess the risk-benefit of these drugs. The other comparative safety studies, between acetylcholinesterase inhibitors versus N-methyl-D-aspartate receptor antagonists and between galantamine and donepezil versus rivastigmine will also contribute to decision making of clinicians and can be the base of other prospective head-to-head comparison studies.
Relevance and aplicability: Population-based cohort studies that use routinely collected health care data have gained importance in the last years because of their ability to provide evidence that could not be generated through randomized controlled trials. This is more important in pharmacoepidemiology given that subjects that are included in the pivotal trials of the drugs usually differ greatly from the overall population that finally receives the medication. The ageing of the populations foresees an increase in the cognitive related disorders including dementia and Alzheimer disease. Although the actual medications to treat dementia (rivastigmine, galantamine, donepezil and memantine) were commercialized more than a decade ago, few are the studies that have analysed their real-world adverse effects at a population level, none of them in Spain, and even fewer are the ones that have done this comparing the different medications. Regardless of the new therapies that are being recently developed to treat dementia the great burden of the treatment still relies on these four medications and therefore is it necessary to fully identify, describe in depth the patients that are using these drugs. The comparative safety analysis results will help health care providers and clinicians to assess the risk-benefits of these drugs to avoid future adverse events or better target patients who receive medication. At last, this can also be a hypothesis generating study given that it will help identify the characteristics of the population at an increased risk of adverse events which could help design future antidementia drug studies.

Objectiu:
Avaluar el grau d’acord del diagnòstic de gota registrat a l’estació clínica d’atenció primària amb el codi M10.0 o M1A.0 i subtipus (classificació CIM10), amb els criteris de classificació de la gota EULAR/ACR 2015 .
Mètodes:
Estudi retrospectiu observacional, per estimar el percentatge de pacients que compleixen els criteris de classificació de gota, entre els que tenen registrat un diagnòstics de gota (M10.0 i M1A.0) a la història clínica informatitzada, en 7 equips d’Atenció Primària de la ciutat de Barcelona.
Es seleccionaran 289 individus aleatòriament, amb el diagnòstic, i es valorarà per mitjà de la història clínica i entrevista telefònica, quin percentatge compleixen els criteris de classificació EULAR/ACR 2015 de gota. Aquests criteris es basen en una puntuació a partir d’una sèrie de preguntes clíniques i dades de proves complementàries. Valors de 8 o per sobre permeten classificar al malalt com a gotós.
També es valorarà el percentatge de malalts que reben tractament reductor de la uricèmia i els canvis en les principals mesures de desenllaç, especialment la uricèmia, en diferents períodes de temps.
Resultats esperats:
Esperem que aproximadament un 75% de les persones amb un codi diagnòstic de gota a la historia clínica d’Atenció Primària, compleixin criteris EULAR/ACR.

Impacte potencial esperat:
Malgrat la gota es una patologia prevalent, amb una incidència en augment i amb una clínica que va més enllà de l’articular, hi ha poc coneixement sobre la seva patologia, les seves associacions i el seu maneig. Validar el codi diagnòstic a les històries clíniques d’Atenció Primària, és el punt de partida per conèixer les característiques clíniques i les associacions amb altres patologies i tractaments, i a partir d’aquí poder detectar punts de millora en el seu maneig.

We aim to estimate the risks of long-term COVID-19 outcomes among individuals with COVID-19 or exposed to COVID-19 during pregnancy, as well as the effect of vaccines on the development of long COVID and long-term COVID-19 outcomes.
Data will be obtained from SIDIAP, which includes primary care records for approximately 6 million people in Catalonia. To estimate long-term COVID-19 outcomes (Objective 1), we will conduct three population-based matched cohort studies using a target trial emulation design from September 2020 to December 2023. We will match COVID-19 infections to uninfected controls in a 1:5 ratio using propensity score (PS) matching. Cases/controls matched cohorts will include: Objective 1.1: people not vaccinated against COVID-19; Objective 1.2: people vaccinated against COVID-19; and Objective 1.3: newborns (cases: exposed to COVID-19 infection during pregnancy, controls: unexposed). Cohorts will be followed for 2 years. Our outcomes will include autoimmune, cardiovascular, mental, neurological, renal and early-life complications. We will estimate cause-specific Hazard Ratios (HR) for each outcome.To estimate vaccine effectiveness on the development of long COVID, we will first characterise long COVID based on persistent symptoms for >28 days (Objective 2.1). We will then estimate the effect of vaccines on the development of long COVID (Objective 2.2) using a staggered cohort study design. Vaccinated and unvaccinated cohorts will be compared using different PS techniques. We will then calculate HR for long COVID and long-term outcomes.
Our findings will inform preventive strategies and post-acute care pathways, thus contribute to prevent long COVID and improve COVID-19 survivors’ health.

Rationale and Background:
Vaproic acid/valproate-containing medicine (VPA) are first-line treatment for generalised tonic-clonic seizures (epilepsy) and adjunctive therapies in other types of seizures. They are also used as second-line treatments or adjuncts for the treatment of bipolar disorder, and for migraine prevention. Valproic acid is a teratogen, with prenatal exposure carrying a substantial risk of neurodevelopmental impairment and congenital malformations in the child. Therefore, its use in women of childbearing age is restricted to prevent valproate exposure during conception and pregnancy.
The European Medicines Agency (EMA) has issued risk minimisation measures in 2014 and 2018 including a compulsory pregnancy prevention program. Timely information on the use of VPA in young women across Europe is important.

Research question and Objectives:
The objectives of this study are
1. To estimate the population-level use (incidence rate and prevalence) of VPA in women between 12 and 55 years of age
2. To characterise patient-level VPA use in women between 12 and 55 years of age initiating treatment with VPA.

Research Methods:
Study design
• Population level cohort study (Objective 1, Population-level VPA utilisation)
• New user cohort study (Objective 2, Patient-level VPA utilisation)
Population:
Population-level utilisation of VPA and alternative treatments: All women aged between 12 years and =55 years between 01/01/2010 and 31/12/2022, with at least 365 days of prior history before the day they become eligible for study inclusion (study period: 2009-2022 including 1 year of previous data). For incidence, anyone with prior use of VPA will be excluded from the analysis.
Patient-level VPA utilisation: New users of VPA in the period between 01/01/2010 and 31/12/2021 (or latest date available), with at least 365 days of visibility prior to the date of their first VPA prescription, and no used VPA in the previous 365 days.
Variables
Drug of interest: Valproic acid, Sodium valproate, Magnesium valproate, Valproate semisodium and Valpromide
Alternative treatments: Carbamazepine, Phenobarbital, Phenytoin, Primidone, Clobazam, Clonazepam, Eslicarbazepine acetate, Lamotrigine, Oxcarbazepine, Perampanel, Rufinamide, Topiramate, Zonisamide, Brivaracetam, Ethosuximide, Gabapentin, Lacosamide, Levetiracetam, Pregabalin, Tiagabine, Vigabatrin, Lithium, Quetiapine, Olanzapine, Lamotrigine, Propranolol, Metoprolol, Atenolol, Nadolol, Timolol, Bisprolol, Topiramate, Amitriptyline, Flunarizine, Pizotifen, Clonidine
Data sources
1. Integrated Primary Care Information Project (IPCI), The Netherlands
2. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain
3. IQVIA Longitudinal Patient Database Belgium (IQVIA LPD Belgium), Belgium
4. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany
5. Hospital District of Helsinki and Uusimaa (HUS), Finland
6. Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom
Sample size
No sample size has been calculated. Feasibility counts have been generated in the general population in each databases.
Data analyses
For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.
Population-level VPA utilisation: Annual period prevalence of VPA use and alternative treatments will be estimated, as will annual incidence rates per 100,000 person years.
Patient-level VPA utilisation: Large-scale patient-level characterisation will be conducted. Medical History will be assessed for anytime – 366 days before index date, for 365 to 31 days before index date, for 30 to 1 day before index date, and at index date. Medication use will be reported for 365 to 31 days before index date , for 30 to 1 day before index date, and at index date. Frequency of indication, namely epilepsy, bipolar disorder and migraine at index date will be assessed. Initial dose/strength and treatment duration will be estimated and the minimum, p25, median, p75, and maximum will be provided.

Rationale and Background
Substantial uncertainty surrounds the prevalence of rare blood cancers. Using real-world data, brought together as part of DARWIN EU®, we aim to estimate the prevalence of rare blood cancers in order to see if they still meet the condition to be classified as a rare disease.
Research question and Objectives
Research question
What is the prevalence of rare blood cancers in Europe?
Study objectives
Objective 1: To estimate the prevalence of follicular lymphoma between 1st January 2010 and the end of available data in data sources from across Europe, stratified by age and sex
Objective 2: To estimate the prevalence of diffuse Large B-Cell Lymphoma between 1st January 2010 and the end of available data in data sources from across Europe, stratified by age and sex
Objective 3: To estimate the prevalence of multiple myeloma between 1st January 2010 and the end of available data in data sources from across Europe, stratified by age and sex
Objective 4: To estimate the prevalence of chronic lymphocytic leukaemia between 1st January 2010 and the end of available data in data sources from across Europe, stratified by age and sex
Objective 5: To estimate the prevalence of acute myeloid leukaemia between 1st January 2010 and the end of available data in data sources from across Europe, stratified by age and sex
Objective 6: To estimate the prevalence of acute lymphocytic leukaemia between 1st January 2010 and the end of available data in data sources from across Europe, stratified by age and sex
Research Methods
Study design
Population-based cohort
Population
All people in a database will be eligible for inclusion in the study. Included study participants will need to have some observation time during the study period and, for the primary analysis, have a year of prior history available. In sensitivity analyses the requirement for prior history will first be removed, and then increased to three years.
Variables
Two age groupings will be used in the study: 1) 0-9; 10-19; 20-29; 30-39; 40-49; 50-59; 60-69; 70-79; 80-89; 90-99; 100+, and 2) 0-44; 45-64; 65 and over. The sex (male/ female) of study participants will also be identified.
Study outcomes will be identified based on the presence of a relevant diagnosis or observation. For the primary analysis, 5-year partial prevalence will be estimated and so individuals will be considered as a prevalent case if they have had a such a record in the prior 5 years. In sensitivity analyses, 2-year partial prevalence and complete prevalence will be estimated. For the latter, once identified as a case, an individual will remain so until their exit from the study (i.e. considering people diagnosed with malignancies to always be affected by the condition).
Data sources
1. Integrated Primary Care Information Project (IPCI), The Netherlands
2. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP), Spain
3. The Clinical Practice Research Datalink (CPRD) GOLD database
4. IQVIA LPD Belgium
5. IQVIA DA Germany
Sample size
No sample size has been calculated as this is a Disease Epidemiology Study where we are interested in the prevalence of haematological cancers in as large and representative a denominator population as possible.
Data analyses
In line with EMA guidelines for the estimation of the prevalence of rare disease, point prevalence will be used for the primary analysis. The prevalence of each outcome of interest calculated on an annual basis as of the 1st January for each year, estimated overall and stratified by age and sex. As a sensitivity analysis annual period prevalence will also be estimated. A minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.

Rationale and Background
The WHO 2021 AWaRe classification (who.int) of antibiotics for evaluation and monitoring of use classifies 258 antibiotics into 3 categories (Access/Watch/Reserve) according to their impact on antimicrobial resistance. The Watch list includes antibiotic classes that have higher resistance potential and includes most of the highest priority agents among the Critically Important Antimicrobials for Human Medicine and/or antibiotics that are at relatively high risk of selection of bacterial resistance. These medicines should be prioritized as key targets of stewardship programs and monitoring. This study will improve our understanding of the use of antibiotics in the Watch category in routine health care delivery, including indication, treatment duration and trends over time. The results will contribute to the EU efforts to monitor use of antibiotics as part of the global fight against antimicrobial resistance.
Research question and Objectives
The objectives of this study are (i) To investigate the incidence and prevalence of use of antibiotics (from the WHO Watch list) stratified by calendar year, age, sex and country/database during the study period 2012-2021. (ii) To explore duration of antibiotic use as well as indication for antibiotic prescribing/dispensing.
Research Methods
Study design: ? Population level cohort study (Objective 1, Population-level drug utilisation study on antibiotics) ? New drug user cohort study (Objective 2, Patient-level drug utilisation analysis with regard to duration and indication of antibiotic use)
Population
Population-level utilisation of antibiotics: All individuals present in the database in the period between 01/01/2012 and 31/12/2021 will be included in the analysis after 365 days of database history. For this population, incidence of use of antibiotics will be explored.
Patient-level antibiotic utilisation: All new users of antibiotics after not using the antibiotic of interest for 30 days in the period between 01/01/2012 and 31/12/2021, with at least 365 days of visibility prior to the date of their first antibiotic prescription.
Variables
Drug of interest: All antibiotics from the WHO Watch list (see also section 9.3.1 – exposure)
Data sources
1. Integrated Primary Care Information Project (IPCI), The Netherlands 2. Bordeaux University Hospital France 3. Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP)-OMOP, Spain 4. Parc Salut Mar Barcelona, Hospital del Mar (IMIM) (hospital database), Spain 5. IQVIA Disease Analyzer Germany (IQVIA DA Germany), Germany, 6. Clinical Practice Research Datalink GOLD (CPRD GOLD), United Kingdom
For all analyses a minimum cell count of 5 will be used when reporting results, with any smaller counts obscured.

Rationale and background: DKP-TRAM is a pharmacologi¬cal fixed association with analgesic activity, which has been registered for treatment of acute pain in 2017 in several European Countries. In Spain and Italy, the product has been launched in January 2017 and March 2017, respectively. The safety and efficacy of DKP-TRAM (25 mg – 75 mg) combination has been extensively demonstrated in the clinical development program in more than 1800 patients, especially from randomized clinical trials (RCTs) in post-operative pain. However, there is limited evidence in the real-life use of the product in the primary care settings particularly in elderly patients where the use of the 75 mg dose (with no possibility of dose titration) of tramadol contained in the combination could be a source of safety concerns for the prescribers.
In the light of this background, the evaluation of the patterns of use and the safety profile of DKP-TRAM combination will be investigated through a real-world study involving an Italian and a Spanish database.
Furthermore, we will test the potential effect modification exerted by age (75 years or older vs. younger patient) or frailty (mild, moderate, severe) among elderly patients (aged 65 or older) on the risk of adverse events (AEs) likely due to DKP-TRAM.
Research question and objectives:
Primary objectives: To evaluate pattern of drug use (i.e. indication, dosage, and duration) of DKP-TRAM.

Secondary objectives:
? To assess the risk of AEs (nausea, vomiting, diarrhoea, vertigo, hallucinations, somnolence, and constipation) in incident users of DKP-TRAM vs. incident users of tramadol as monotherapy and fixed combination tramadol-paracetamol.
? To evaluate the effect modification exerted by age (75 or older vs. 74 or younger) on the risk of adverse events in DKP-TRAM vs. tramadol monotherapy and tramadol-paracetamol combinations users.
? To evaluate the effect modification exerted by frailty (mild, moderate or severe) on the risk of adverse events in DKP-TRAM vs. tramadol monotherapy and tramadol-paracetamol combinations users aged 65 years or older.

Background: The overwhelming numbers of COVID-19 infections have led to an unprecedented crisis for healthcare systems worldwide. Understanding the impact of this pandemic on health is an urgent priority.
Objectives: UNCOVER aims to unravel the mid- and long-term effects of the pandemic on COVID-19 and non-COVID-19 morbidity and mortality through the use of large real-world databases from Catalonia and the UK.
Methods: UNCOVER will conduct a cohort study using longitudinal electronic health records from Catalonia (SIDIAP) and the UK (CPRD). These databases have been transformed to an international common data model (CDM), and when possible, the study will be replicated in other databases around the world. COVID-19 testing, diagnosis in primary care, hospitalisations, and deaths will be identified from March 1st 2020. Study periods will be defined as pre-COVID-19, COVID-19-pre-vaccine, and COVID-19-vaccination. Different periods will be defined for the study of non-pharmaceutical interventions by country. Mid- and long-term symptoms and outcomes will be identified. Time-series and multi-state models will be used for data analyses.
Expected results: UNCOVER will provide novel scientific knowledge aimed at helping decision-makers and clinicians in the control and management of the pandemic on a national and international level, whilst improving populations’ health and quality of life.

Osteoarthritis (OA) is the most common arthritis and a major cause of disability in older people. However, apart from a few cross-sectional studies, little research has been done into its comorbidities. A recent meta-analysis study from Weiya Zhang’s team in Nottingham found out that 67% people with OA have other chronic diseases, which is about two times more than an age/gender matched control without OA. However, whether these comorbidities just co-exist with, share common risk factors, cause or are consequences of OA remains unknown. Therefore, we propose a multi-centered research project of cohort and/or case-control studies using primary care data from SIDIAP platform (Information System for the Development of Research in Primary Care). We aim to examine 1) prevalence and incidence of comorbidities in OA and time sequence between OA and comorbidities; 2) common clusters and impact of comorbidities in people with OA; 3) association between commonly used OA analgesics and comorbidities and these three aims will be answered in three working packages (WP1-3). The statistical analysis plan are described in more details in the methodology section V of this protocol.
In this multi-centered project funded by FOREUM (Foundation for Research in Rheumatology), the SIDIAP platform will be used for WP 1-3, together with the other three national/regional registration databases in the UK, Netherlands, and Sweden. Finally, data from different countries will be meta-analysed for consistency among countries (WP5). The heterogeneity and generalisability of the results (as well as other sites) will be a crucial issue and need further discussion.

? 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).

Background: Anticoagulation with Vitamin K Antagonists (VKAs), including acenocoumarol, phenprocoumon and warfarin, has been the standard of care for more than 60 years. Limitations of VKA treatment include bleeding events and close monitoring of therapeutic levels. Direct oral anticoagulants (DOACs), which have been on the market since 10 years, do not require close monitoring. DOACs include factor II inhibitors (i.e. dabigatran) and factor Xa inhibitors (i.e. apixaban, rivaroxaban and edoxaban). Daiichi Sankyo Europe (DSE) conducted an analysis on HOKUSAI-VTE trial(1) data with the aim to identify effect modifiers of the effectiveness (i.e. VTE recurrence) and safety (i.e. clinically relevant bleeding) of edoxaban or warfarin (a VKA) treatment. The analyses established that age and creatinine clearance modified the treatment effect for VTE recurrence and creatinine clearance the treatment effect for clinically relevant bleedings. In an analysis among AF patients, using the ENGAGE AF-TIMI 48 trial data(2), exploratory analyses suggested lower effectiveness (i.e. prevention of stroke and systemic embolism) with higher-dose edoxaban regimen compared with warfarin at higher levels of creatinine clearance.

Hypotheses and objectives: DSE has the working hypotheses that the effect modification established also applies to patients with AF and current VKA-based network meta-analyses are not correct as these were not corrected for this effect modification. Objectives of this study are to assess effect modification of the safety of DOAC versus VKA treatment in patients with AF; and assess effect modification of the effectiveness of DOAC versus VKA treatment in patients with AF.

Methods: Patients with DOAC or VKA recorded dispensings between 2011 and 2017 will be selected in the PHARMO Database Network, HSD, and SIDIAP. Adult patients with an AF indication will be included in the study. Patients will be followed until the end of the first treatment episode of their VKA/DOAC.
Measurements: Age, gender, eGFR, liver values, weight and CHADVASc score will be considered as effect modifiers. Effectiveness and safety outcomes will be assessed.
Statistical analyses: Effect modification will be tested by including interaction terms between VKA/DOAC and the potential effect modifier in cox proportional hazard models.

Expected outcomes: Modification of the safety and/or effectiveness of DOACs and VKAs will be expected due to some effect modifiers.
Applicability and relevance: When effect modification exists, healthcare providers need to take this into account when prescribing a DOAC or VKA for patients with AF.

BACKGROUND: Galcanezumab is a humanised monoclonal antibody against human calcitonin gene-related peptide (CGRP) and is indicated for the prophylaxis of migraine in adults who have at least 4 migraine days per month and is currently under evaluation for the preventive treatment of episodic cluster headache. As migraine and cluster headache (CH) are chronic conditions, continuous or intermittent long-term treatment is anticipated in routine clinical practice. Exposure to galcanezumab was limited in clinical trials. Therefore, infrequent adverse effects and effects which have a longer latency period, such as serious hypersensitivity and/or malignancy, could occur in real-world practice. Additionally, patients with recent cardiovascular (CV) events and/or serious CV risk as well as patients over the age of 65 years, who were excluded from the clinical trial population, might be part of the user population in everyday clinical practice. The implications of long-term inhibition of CGRP are unknown, including the impact on long-term safety. As a result, the long-term safety of galcanezumab in larger patient populations requires further characterisation.
Research question and objectives: The purpose of this study is to evaluate the utilisation and safety of galcanezumab with respect to serious hypersensitivity events and long-term safety (up to 5 years), including malignancy and cardiovascular events in routine clinical practice in Europe. The primary objective is to characterise the utilisation of galcanezumab for the treatment of migraine or CH and to assess the incidence of serious CV events, serious hypersensitivity reactions, and malignancies in real world clinical practice in Europe.
This objective is primarily descriptive and aims to assess:
? the utilisation of galcanezumab overall and in special populations of interest, particularly: o patients with recent (within the last 6 months) serious CV events and/or serious CV risk prior to initiating galcanezumab o patients ?65 years of age
? the incidence of serious CV events in patients who receive galcanezumab treatment overall, by duration of galcanezumab treatment and in the special populations of interest including:
– patients with recent (within the last 6 months) CV events and/or serious CV risk prior to initiating galcanezumab
– patients ?65 years of age
? the incidence of serious hypersensitivity reactions such as anaphylaxis in patients who receive galcanezumab
? the incidence and distribution of time to malignancies (excluding non-melanoma skin cancers) in patients exposed to galcanezumab
The secondary objective is to provide context for incidence rates of safety events seen in the galcanezumab-exposed migraine cohort by describing the incidence rates observed in a comparator cohort of migraine patients that initiated another (prophylactic) migraine medication and, as feasible, to conduct comparative safety analyses of serious CV events, and malignancies. Non CGRP prophylactic migraine medications are small molecules that are typically less immunogenic than monoclonal antibodies. There is also uncertainty around the ability to accurately identify serious hypersensitivity events. As such, formal comparative analyses are not proposed; however, rates in the comparator cohort will be provided for context.
STUDY DESIGN: An observational cohort study using data from various population-based healthcare databases from seven different European countries.
POPULATION: The study population for the primary objective will include all patients with a prescription or dispensing of galcanezumab in the population-based healthcare databases from seven different European countries including France (FR), Germany (DE), Italy (IT), the Netherlands (NL), Spain (ES), Sweden (SE) and the United Kingdom (UK). This cohort will be divided into three sub-cohorts based on the diagnosis and/or treatment of migraine or CH. In addition, sub-cohorts of patients with recent (within the last 6 months) serious CV events and/or serious CV risk prior to initiating galcanezumab and patients ?65 years of age will also be created. The study population for the secondary objective will include all migraine patients initiating treatment with galcanezumab in the population-based healthcare databases from the seven different European countries. To provide context for incidence rates of the safety events seen in the galcanezumab-exposed migraine cohort, migraine patients who initiate treatment with comparator medication topiramate, will be used as a comparator cohort for analyses of serious cardiovascular events and malignancies. A formal comparative analysis for serious hypersensitivity reactions will not be undertaken due to the lack of an appropriate comparator and uncertainty around the ability to accurately identify these events. Rates in the comarator cohort will be provided for context. For each of the databases, the study period starts at the time galcanezumab was approved by the European Commission (i.e. 14 November 2018). The end of the study period will depend on the available data at the end of data collection (Q3 2025) for each country. Assuming an average data lag time of approximately 1.5 years, the end of the study period will be Q4 2025 at maximum.
VARIABLES:
– Exposure
Primary objective: The exposure of interest will include any treatment with galcanezumab. Secondary objective: The exposure of interest will include new users of galcanezumab or comparator medication topiramate. Patients will be considered to be new users if they have not been prescribed/dispensed their index drug within the 12 months prior to the index date (i.e first prescription/dispensing of galcanezumab or comparator medication within the study period).
– Outcomes
The outcomes of interest are serious CV events, serious hypersensitivity reactions and malignant neoplasms. Serious CV events under consideration include: hospitalisation for: myocardial infarction (MI), transient ischaemic stroke (TIA), ischaemic stroke, ischaemic heart disease, unstable angina pectoris (AP), percutaneous coronary intervention (PCI), coronary revascularisation and CV death. The final selection of CV outcomes will depend on the accuracy of the diagnosis within in each data source. Serious CV events will be reported as composite and individual outcomes. Serious hypersensitivity reactions will be identified by a hospitalisation or emergency care visit for anaphylaxis or allergy. As feasible, hospitalisations or emergency care visits for angioedema, acute asthma or acute bronchospasm, acute upper airway obstruction, epinephrine administration and death from serious hypersensitivity reactions (i.e. death after any of these events, to be detailed in the SAP) will additionally be assessed as part of this outcome. Malignant neoplasms will be identified as a diagnosis of any cancer, excluding non-melanoma skin cancer (NMSC). Malignancies will be reported as a composite outcome (all malignancies, excluding NMSC), and by type of the first malignancy (i.e. per primary cancer site). All outcomes of interest will be identified by using the database specific coding systems (e.g. READ codes in the UK, International Classification of Diseases (ICD) 9 th or 10th revision, or International Classification of Primary Care (ICPC) in the Netherlands), as well as the specific provenance of the data (e.g. hospital admission, primary care or emergency care visits). The specific diagnostic codes to identify the outcomes of interest will be included in the statistical analysis plan (SAP). Furthermore, table shells will be provided in this document to show which results will be delivered.
– Covariates
Demographic and clinical covariates will be considered for descriptive purposes and as confounders in the comparative study. All available data prior to start of the treatment will be used to assess baseline demographics and clinical covariates.
DATA SOURCES: All data will be obtained from seven European databases. The following databases will be used: ? SNDS (Système National des Données de Santé) from France
? GePaRD (German Pharmacoepidemiological Research Database) from Germany
? ARS (Agenzia regionale di sanità della Toscana database) from Italy
? PHARMO (The PHARMO Database Network) from the Netherlands
? SIDIAP (Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària) from Catalonia, Spain
? SHR (Swedish Health Registers) from Sweden
? CPRD (The Clinical Practice Research Data Link Gold plus Hospital Episodes Statistics (HES) Data) from the UK
STUDY SIZE: The number of galcanezumab-exposed patients will depend on the uptake of galcanezumab in each country. The descriptive outcomes in the primary objective as well as the incidence rates as part of the secondary objective will be presented in the final report regardless of the size of the study population. The comparative analyses will only be performed if target sample sizes are attained that will allow us to detect a 2-fold difference in this primary outcome of serious CV events with 80% power for the composite endpoint of serious CV events (N = 7,245 person-years in galcanezumab-exposed patients per database). Pooled analysis or meta-analysis will be considered to help achieve sufficient power, depending on the appropriateness of combining data sources.
DATA ANALYSIS: Descriptive statistics for demographic and clinical characteristics at baseline will be provided. Incidence rates for serious CV events, serious hypersensitivity reactions and malignant neoplasms will be presented for the galcanezumab-exposed migraine and topiramate migraine cohort and will be estimated by dividing the number of events of interest by the person-time at risk. If feasible, based on accrual of target sample size, comparative analyses will be conducted to compare the incidence of serious CV and malignancy events among migraine patients that are new users of galcanezumab with propensity score-matched new users of topiramate. This will be further detailed in the SAP. Relative risks for the outcomes of interest will be estimated as hazard ratios (HRs). All analyses will be done for each country separately as well as pooled (if deemed appropriate based on the similarity of results and outcome definitions).

Motius i antecedents
Els nivells elevats de eosinòfils sanguinis (és a dir eosinofília) estan associats amb un augment del risc d’exacerbacions (greus) d’asma, especialment en pacients amb asma no controlada o parcialment controlada a la línia de base. Encara que hi ha una sèrie d’estudis que han investigat l’associació entre els eosinòfils sanguinis i el risc d’exacerbació d’asma, pocs estudis han investigat l’associació amb la mortalitat. A més, l’associació entre asma tardana (en pacients amb eosinofília) i risc d’exacerbacions d’asma encara no s’ha investigat a la vida real. Finalment, és menys conegut si els nivells d’eosinòfils sanguinis es redueixen en pacients amb asma tractats amb ICS d’alta dosi.

Background:
The use of opioids has increased dramatically, especially in Spain; between 2008 and 2015 the use of opioids increased an 83.5%. These medications have many adverse effects and there are few head to head studies with other non-opioid pain killers.
Hypothesis: The use of opioids is frequent in our populationa. Opioids have more adverse effects than other non-opioid pain killers.
Objectives: 1. To describe the drug utilization (sociodemographic, type, dosage, indications, persistence) of opioids (tramadol, codeine, morphine, fentanyle) (WP1) among subjects of at least 18 years old. 2.To assess the incidence of the adverse effects of the different opioids and compared with other non-opioid pain killers (oral NSAID, cox2 inhibitors, paracetamol, metamizole). To study the association between the long term use of opioids and paracetamol. All results will be stratified by indication and age.
Methods: A population based cohort study. The WP2 will encompass 3 cohorts: 1. incident opioid users, 2. incident non-anti-inflammatory drugs and 3. incident anti-inflammatory drug users. Data will be gathered from the SIDIAP database. Source population: All those registered at least 1 year in SIDIAP database during the study period. Study period: 01/01/2007-31/12/2016. Study population: all incident users of study drugs durgin the study period aged 18 and over. Inclusion: at least 2 consecutive dispensations of the study drugs during the study period. For the WP2 (in addition of the above): No use of index drugs in the previous year, no surgery in the 30 days before starting their first dispensation. No exclusions. Follow-up: from the lastest of 1. Start of study period or 1 year of valid data, until the earliest of: end of enrolment in database (moving out or death) or date of last data capturing. For the WP2: patients will be followed from the date of second drug dispensation which follows the latest of 1. start of study period or 1 year of valid data, until the earliest of 1.end of enrolment in the database, date of last data capturing or event of interest. Variables: Exposures: WP1: the main drugs of interest will be the opioids and the non-opioid pain killers will be the active comparators for the WP2. The exposure will be categorized in past, recent, current. Patients switching treatment will be censored at the date of switching. Concomitant use of drugs will be assessed and considered for secondary analysis. Outcomes: WP1: age, sex, BMI, Charlson Comorbidity Index (CCI), eFi frailty index, pfeiffer and minimental score, EQ5D, type and dosage of opioid used, type of prescriber, comorbidity for which the opioid was prescribed. In order to define periods of continious use of drugs, any 2 dispensations of the same drug will be concatenated if the gap is <90 days. A carry-over period of 30 days will be added after last prescription to account for lack of compliance and carryover effects. Compliance will be measured as medication possesion ratio. WP2: Cardiac arrhythmia, delirium/confusion, fractures (hip, pelvis, wrist, humerus), falls, sleep disorders (sleep apnea, somnolence), constipation, opioid dependence and abuse, all cause mortality. Potential confounders (in the year before index date): age, sex, BMI, sociodemographic status, medical conditions, CCI, bone fractures, major surgeries, drugs (hypnotics, benzodiacepines, aspirin, SSRI or anticonvulsant), number of different ATC prescribed, number of GP visit, hospital admisions, falls, traffic accidents. Statistical analysis: Kaplan Meier for drug persistence, Drug safety: Propensity score will be calculated using confounders. Cox regression will be used to estimate event risk according to drug use.

La diabetes mellitus tipo 2 (DM2) y la osteoporosis son dos patologías frecuentes en nuestras consultas. En los últimos años se ha descrito un mayor riesgo de fracturas en los pacientes DM2, si bien la evidencia de los diferentes fármacos para la osteoporosis (FPO) en estos pacientes es limitada. Nuestro objetivo es analizar si existen o no diferencias en la incidencia de nuevas fracturas en los pacientes que inician un FPO, en función de la presencia de DM2 o no.
Estudio de cohortes retrospectivas de base poblacional realizado en el ámbito de la Atención Primaria de Salud. De la base de datos SIDIAP se seleccionarán aquellos pacientes que inicien un FPO entre 2012-2015, identificando aquellos DM2 y se emparejarán por propensity scores con 5 sujetos no diabéticos. Se recogerá información sobre fracturas incidentes (variable respuesta), datos sobre FPO y variables confusoras. El intervalo incluido para el análisis de incidencia de fracturas será el período de tratamiento, comparando el período de referencia (0-6 meses) con el intervalo de 6 meses hasta el final
del tratamiento o final del estudio. La incidencia acumulada de fracturas principales se estimará mediante el análisis de Kaplan-Meier. Mediante Cox se calculará el riesgo de fractura, ajustando por edad, sexo, índice de masa corporal, uso de corticoides orales, fractura previa, condiciones de comorbilidad y tratamientos antidiabéticos, para cada una de las cohortes expuestas (DM2 y no diabéticos), y se comparará a los controles emparejados por propensity score.

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.

Justificació: La supervivència dels pacients amb aturada cardio-respiratoria (ACR) sobtada extra-hospitalària es pot augmentar mitjançant la formació en matèria de RCP dels cuidadors principals del pacients amb risc de ACR. Englobat dins d?un assaig clínic que vol determinar l´efectivitat d´una xarxa de voluntaris activats mitjançant una aplicació mòbil en la reducció del temps d´inici de les maniobres de RCP es realitzarà una formació en RCP i us del DEA a familiars o cuidadors principals de pacients amb malaltia cardíaca de reus.

La formació es realitzarà a 430 persones i serà feta per formadors del Consell Català de Ressuscitació (CCR). Els voluntaris assistiran a unes sessions teòrico-pràctica (amb maniquí) amb una durada de dos hores, en grups de 15 voluntaris i dos docents acreditats pel CCR com a Formadors. Es faran en total 30 sessions per formar unes 430 persones. Un cop finalitzat cada curs formatiu en RCP-DEA s´oferirà la participació voluntària en la Xarxa-RCP. Esperem la captació d’unes 100 persones (25% dels formats).
També es convidarà a participar en la xarxa als estudiants de la Facultat de Medicina de a Universitat Rovira i Virgili de Reus, el personal sanitari dels Centres d´Atenció Primària de Reus i els membres del Cossos de Seguretat que reben una formació en RCP bàsica i ús de DEA.
Un cop finalitzada la formació en RCP es avaluarà les competències adquirides mitjançant una simulació al centre de la ciutat.

La herramienta de cálculo de riesgo FAX (R) ha sido sujeto de evaluación en los últimos años con resultados insatisfactorios en diversas poblaciones españolas. Además, para su cálculo se requiere de entrevista clínica y prueba/s de imagen para su cálculo.

OBJETIVO: Desarrollar y validar una herramienta predictiva de fracturas osteoporóticas en población española en base a datos disponibles en historia clínica informatizada de atención primaria (HCAP), implantable para su cálculo automático en HCAP.

STUDY AIM/s:
In line with the proposed topic (3.3.4) of CIBERFes on «»Advanced data analysis and management systems (Big Data solutions) in the identification and assessment of frailty risk profiles in populations, their evolution to disability, and their treatment»»), we propose the following four aims:
1.ASSESSMENT OF FRAILTY RISK PROFILES:
1.1.To validate the Rosen, Dubois, ERA and eFI frailty indices in our population by testing their validity to predict key features of the frailty phenotype (Rockwood et al [ref]) including: co-morbidity, cognitive impairment, disability, and geriatric syndromes (falls, delirium, and/or urinary incontinence) in our population aged >75 years.
1.2.To characterise the descriptive epidemiology of frailty as defined by the previously validated indices (1.1) by estimating the point prevalence and annual incidence rate of frailty after stratification by age (5-year bands), gender, and socio-economic status (quintiles of national MEDEA deprivation score).
2.EVOLUTION FROM FRAILTY TO DISABILITY
2.1.To study the impact of frailty (as defined by previously validated indices above) on the risk of subsequent severe falls (leading to GP contact/s and/or hospital admission), fracture/s, and all-cause mortality in an elderly population aged >75 years.
AND 3.TREATMENT OF FRAILTY
3.1.To study the association between oral bisphosphonate use and the risk of fracture/s and all-cause mortality amongst patients previously identified as frail (as defined above) amongst elderly people aged >75 years.

SUMMARY OF METHODOLOGY:
-Study Design: Population-based cohort study using de-identified primary care records linked to pharmacy dispensations and hospital admissions data for >80% of the population of Catalonia (SIDIAP database).
-Data Source/s: SIDIAP (Sistema de Informacion para el Desarrollo de la Investigacion en Atencion Primaria) contains de-identified information on socio-demographics (year of birth, gender, country of origin, socio-economic status, etc), lifestyle risk factors (smoking, alcohol drinking, physical activity, etc), clinical measurements (height, weight, waist circumference, blood pressure, etc), co-morbidity (recorded diagnoses using ICD-10 codes), prescriptions, and linked community pharmacy dispensations (as coded using the World Health Organization ATC catalogue). SIDIAP holds data on a total of 884,687 people aged >75 in the period 2007-2014, and contributing staff (nurses and primary care physicians) have ?as part of routine practice- collected information on activities of daily living (Barthel) and cognitive function (Pfeiffer test) for a substantial 354,457 (40%), and 346,576 (39%) of them respectively. This, linked to hospital admissions data, constitutes a unique dataset for the study of frailty, its impact, and its possible treatment in community-dwelling elderly patients.
-Participant/s: all patients aged >75 and registered in SIDIAP in the study period (2007-2015) will be eligible for Aims 1.1, 1.2 and 2.1. Previous users (before categorized as ?frail?) of anti-osteoporosis medications (except calcium/D supplementation) will be excluded for Aim 3.1.
-Study Outcome/s: the three proposed frailty indices will be validated against the Rockwood frailty criteria, which will therefore be study outcomes for Aim 1.1, to include: co-morbidity (as measured using the Charlson co-morbidity index), cognitive impairment (Pfeiffer score), disability (Barthel), and geriatric syndromes (falls, delirium, and/or urinary incontinence, all three identified using ICD10 codes in medical records).
Outcomes for Aims 2.1 and 3.1 will include severe fall/s, fracture/s (both identified using ICD10 codes), and all-cause mortality (as based on linked administrative data).
-Exposure/s: the proposed frailty indices will be the main exposure/s for Aims 1.1 and 2.1. The Rosen index will be estimated using coded diagnoses (ICD10) in SIDIAP records. Similarly, prescriptions and pharmacy dispensations will be used for the estimation of the Dubois index. Finally, the ERA index will be estimated using socio-demographics (age, gender), previous hospital admissions (from linked hospital data), and past medical history (ICD10 codes in primary care records) recorded in SIDIAP for the study population. Bisphosphonate use will be the exposure of interest for Aim 3.1. Patients will be identified as bisphosphonate users if they collected at least 2 packs of any oral bisphosphonate (ATC codes M05BA except M05BA03 and M05BA08 as these are intravenous and therefore not available in pharmacy dispensation/s data) in the study period.
-Co-variables/Confounders: lists of a priori-defined confounders will be established for each of the study Aims based on previous literature and clinical knowledge within research team members. A propensity score for bisphosphonate use will be calculated to minimize confounding in Aim 3.1.
-Sample size/power: According to feasibility figures provided by SIDIAP, at least 346,576 patients will be available for the validation of frailty indices (Aim 1.1), which requires data on Barthel/Pfeiffer scores. The whole available population aged >75 years (N=884,687) will be included for Aims 1.2 and 2.1, providing very precise estimates of validity (1.1) and prevalence/incidence (1.2). Assuming a 10% prevalence of frailty, and with known 5% annual mortality and 2/1,000 person-years fracture rates in SIDIAP patients of this age [Pages-Castella et al. BMC MSK Disord], these figures provide >99% for the detection of an excess risk of >20% (HR 1.2) as significant in the analysis of the association between frailty and fractures, with even higher power for mortality [Aim 2.1].
According to SIDIAP feasibility numbers, 87,254 bisphosphonate users and 797,433 non-users will be eligible for Aim 3.1. These numbers provide >99% power for the detection of a >5% risk reduction in mortality and >95% for a >15% fracture risk reduction associated with bisphosphonate use in a log-rank two-sided test with assumed 10% drop-outs and up to 8 years of follow-up (drop-out/transfer out was 8.2% in the period 2007-2014).
-Statistical Analyses:
Aim 1.1: Sensitivity, specificity, predictive values (negative/positive) and area under the ROC (receiver operating characteristic) curves will be provided for the validation of each of the frailty indices against each of the Rockwood criteria. Indices with an AUC ROC>70% in their validation against disability, cognitive impairment and at least one geriatric syndrome (see above) will be considered valid for the assessment of frailty.
Aim 1.2: Point (on last day before data extraction) prevalence and average annual incidence rates (for the whole study period) of frailty, as estimated using previously validated index/indices, will be estimated for the whole eligible population (aged >75) and then after stratification by age, gender, and socio-economic status
Aim 2.1: Cox regression and Fine and Gray (accounting for a competing risk with death) models will then be fitted to estimate relative risk of fall/s, fracture/s, and all-cause death according to frailty status
Aim 3.1: Propensity scores will be estimated for bisphosphonate use using logistic regression equations, and propensity score matching methods will be applied to obtain ?comparable? populations of bisphosphonate users and matched non-users. After that, similar survival methods (Cox and Fine and Gray) will be used to estimate the relative risk of fracture/s and death according to bisphosphonate use in the propensity-matched population.
The assumption of hazards proportionality will be checked for all the fitted Cox/Fine and Gray models by graphical visualization of hazard function/s and/or formal testing using Schoenfeld?s residuals.

LCZ696 (sacubitril/valsartan; Entresto®) is a novel treatment initially approved in the United States, the Europe Union (EU) and a number of other countries in 2015. In the EU, Entresto® is indicated in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction.
Based on the observation that sacubitril inhibits OATP1B1 and OATP1B3 transporters in vitro Novartis conducted a drug-drug interaction (DDI) study with atorvastatin (a HMG-CoA reductase inhibitor [statin] in which LCZ696 increased the maximal plasma concentrations (cmax) of the OATP1B1 and OATP1B3 substrates atorvastatin and its metabolites by up to 2-fold. However, the areas under the curve (AUCs) of atorvastatin and its metabolites were not increased to a clinically significant extent (<1.3-fold), suggesting that the impact of sacubitril on the pharmacokinetics of atorvastatin is limited to cmax. Therefore, the EU SmPC recommends ?that caution should be exercised when co-administering Entresto with statins?. To further elucidate the potential of LCZ696 to interact with OATP1B1 and OATP1B3 substrates, Novartis conducted another clinical DDI study ? completed after the Entresto® EU submission ? using simvastatin. Simvastatin is a prodrug and metabolized to the active metabolite simvastatin acid which is a more sensitive OATP1B1 and OATP1B3 substrate. LCZ696 has no clinically significant impact on exposures of both simvastatin and simvastatin acid when simvastatin was co-administered with LCZ696. Based on the atorvastatin study, and given the high proportion of patients expected to be on a concomitant statin post-marketing, the Committee for Medicinal Products for Human Use (CHMP) requested that Novartis consider further evaluation of this potential DDI in the post-marketing setting. In the approved Entresto® EU Risk Management Plan (RMP Version 1.4), Novartis therefore committed to perform a (non-imposed) non-interventional post-authorization safety study (PASS, category 3) dedicated to assess specific statin-associated safety events, namely myotoxicity, and hepatotoxicity, in association with concomitant use of statins together with LCZ696 in patients with HF. In addition, in the Pharmacovigilance Risk Assessment Committee (PRAC) RMP Assessment Report from September 2015, Novartis was asked by the PRAC Rapporteur to ?consider including pancreatitis to the list of statin-related events?.

LCZ696 (sacubitril/valsartan; ATC code C09DX04; Entresto®) exhibits a novel mechanism of action to
treat heart failure (HF) with the angiotensin receptor neprilysin inhibitor (ARNI) by simultaneously
inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug
sacubitril, and by blocking the angiotensin II type-1 (AT1) receptor via valsartan. It was approved in the
European Union (EU) on 19 November 2015. In the EU, Entresto is indicated in adult patients for
treatment of symptomatic chronic heart failure with reduced ejection fraction.
As agreed with the Committee for Medicinal Products for Human Use (CHMP), Novartis will conduct a
non-imposed non-interventional Post-Authorization Safety Study (PASS; category 3) for the risk of
angioedema in association with LCZ696 use. In addition to the risk of angioedema, this study will
investigate the risks of hypotension, hyperkalemia, hepatotoxicity, and renal impairment (all included in
the Risk Management Plan [RMP] for Entresto as ?important identified risks?, except ?hepatotoxicity?
which is listed as ‘important potential risk’).

OBJETIVOS: Distintos ensayos clinicos han demostrado que los medicamentos anti-osteoporosis tienen una efectividad del 50% en reduccion de fracturas. Sin embargo, existe poca información sobre la efectividad y seguridad de dichos fármacos en práctica clínica real en Atención Primaria de Salud (APS).
Objetivos:
Principal: estimar la incidencia de fractura y de efectos secundarios en los usuarios de cada una de estas medicaciones en la práctica clínica diaria.
Secundario: analizar la incidencia de los mismos eventos en subgrupos de población infra-representados en ensayos clínicos: 1.hombres, 2.ancianos, 3.usuarios de corticoides orales, 4.obesos, 5.pacientes con demencia, 6.diabetes tipo 2, y 7.insuficiencia renal.

BACKGROUND AND OBJECTIVE/S Recent analysis of prescription data in Catalonia (Spain) has confirmed that early discontinuation (in the first 12 months of all available osteoporosis therapies (alendronate, risedronate, raloxifene, bazedoxifene, strontium ranelate and parathyroid hormone analogues), is high ranging from 50% to 78% (Carbonell-Abella et al., 2013). It is therefore important to understand the persistence profile of newly introduced drugs such as denosumab compared with other available treatments in real-world clinical practice. Primary Objective: – To estimate 12-month persistence with each of the pharmacological treatments available in primary care (oral and subcutaneous drugs) for post-menopausal osteoporosis in Catalonia (Spain) amongst incident users (both treatment naïve and switchers) of such drugs between January 2012 and December 2012 Secondary Objectives: – To describe demographic and clinical characteristics of patients initiating pharmacological treatment for post-menopausal osteoporosis in Catalonia (Spain) between January 2011 and December 2014 stratified by year of initiation and by drug – To characterize baseline characteristics of those patients who switch from one anti-osteoporosis drug to a different one in Catalonia (Spain) between January 2011 and December 2014 – To characterize baseline characteristics of new users of any anti-osteoporosis medication (available in primary care) in Catalonia (Spain) in the period 2011-2014 who are treatment naive at treatment initiation (with no use of pharmacological treatment/s for post-menopausal osteoporosis in the previous year) – To estimate 24-month persistence with each of the pharmacological treatments available in primary care (oral and subcutaneous drugs) for post-menopausal osteoporosis in Catalonia (Spain) amongst incident users (both treatment naïve and switchers) of such drugs between January 2012 and December 2012 – To estimate persistence at 12 months and 24 months for the patients initiating pharmacological treatment for post-menopausal osteoporosis in Catalonia (Spain) between January 2012 and December 2012 who are treatment naïve at treatment initiation and for the patients who switch from another drug at treatment initiation – To estimate Hazard ratios (HR) for risk of discontinuation (for both treatment naïve patients and switchers) of each treatment at 12 months and 24 months using weekly alendronate (the most commonly dispensed anti-osteoporosis medication in our setting) as the reference group. METHODS -Study Design: Retrospective cohort study of patients initiating any treatment for osteoporosis, based on the Information System for the Development of Research in Primary Care (SIDIAP) database. -Study Population: women 50 years of age or older purchasing ?56 daily doses of any of the anti-osteoporosis treatments available between 1/01/2011 and 31/12/2014 and with no previous use of the same drug in the previous year (ie. new drug users) according to SIDIAP data will be eligible. Users with a previous or active history of bone Paget?s, AIDS, cancer, and/or users of anti-neoplastic drugs (including aromatase inhibitors) will be excluded. -Primary outcome: the main study outcome will be 1-year persistence with the index drug. Persistence (time on treatment) will be estimated as the number of days from first dispensation (drug initiation) to last dispensation (the last before a 3-month refill gap, with a sensitivity analysis at 6-months) + number of DDDs dispensed on the latter. -Data analysis: Kaplan-Meier estimates of cumulative incidence of therapy discontinuation stratified by osteoporosis drug used and by treatment history will be plotted. In order to account for potential confounders, multivariable Cox regression models adjusted for age, gender, body mass index, smoking, alcohol drinking, Charlson co-morbidity index, previous fracture, previous use of anti-osteoporosis medication/s, socio-economic status, and use of oral corticosteroids will be fitted. Multiple imputations will be used to account for missing data for BMI, smoking, alcohol, and MEDEA.

Los pacientes diabéticos tipo 2 (DM2) presentan mayor riesgo de fracturas. Existen pocos datos sobre la eficacia de los fármacos anti-osteoporosis (FOP) en estos pacientes y el efecto de los nuevos fármacos antidiabéticos sobre el riesgo de fracturas. Nuestro objetivo es analizar la efectividad de FOP en DM2 y estudiar el efecto sobre el riesgo de fracturas de los antidiabéticos.

Estudio de cohortes retrospectivas de base poblacional. De la base de datos SIDIAP se seleccionan a todos los pacientes con diagnóstico de DM2 previo a 31/12/2013. En subestudio 1 se seleccionarán todos los DM2 con FOP y se aparearán hasta 5 pacientes DM2 sin FOP con similares características basales. En subestudio 2 se identificarán los pacientes DM2 usuarios de fármacos antidiabéticos y se aparearán hasta 5 DM2 no usuarios de fármacos del mismo grupo con similares características clínicas basales.

La variable resultado será el tiempo desde el inicio del fármaco hasta la aparición de la primera fractura mayor (Center & Eisman). Como variables predictoras se considerarán los diferentes FOP y los antidiabéticos no insulínicos. Se considerarán confusores: edad, sexo, índice masa corporal, consumo de tabaco y alcohol, fracturas previas, complicaciones de la DM2, cataratas y fármacos que aumentan riesgo de caídas o de fractura.
Análisis estadístico: El apareamiento por características basales se realizará mediante propensity scores. El riesgo de fractura después de la fecha índice se calculará para cada una de las cohortes expuestas, y se comparará a los controles apareados por propensity score correspondientes mediante regresión de Cox.

Rationale and background
Strontium ranelate (Protelos®/ Osseor®) has been authorised since 2004 in the European Union for the treatment of osteoporosis in postmenopausal women to reduce the risk of vertebral and hip fracture. Since June 2012, strontium ranelate is also approved for the treatment of osteoporosis in adult men at increased risk of fracture.
In the frame of 13th PSUR assessment, data submitted raised concern regarding cardiovascular safety beyond the already recognised risk for venous thromboembolism. As a result of this assessment, an increased risk for serious cardiac disorders, including myocardial infarction has been identified and risk minimization measures specifically targeting this identified risk were recommended by the CHMP. These risk minimisation measures included a restriction of the target population by excluding patients with established, current or past history of ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease and/or uncontrolled hypertension, and precautions of use. These changes were disseminated in the form of a DHPC in May 2013.
In view of this newly identified risk of serious cardiac disorders, an overall benefit/risk review under Article 20 of regulation (EC) No 726/2004 started in May 2013 and was finalized on 20 February 2014. Following the outcome of this referral, the MAH has to conduct a non-interventional safety study to evaluate the effectiveness of the applied risk minimisation measures.
The overarching aims of the proposed study are:
1. To study the effect of the risk minimisation measures for Strontium Ranelate
2. To estimate and compare the incidence rates of cardiac and thromboembolic events in users of SR and users of bisphosphonates

Research question and objectives
PRIMARY OBJECTIVES:
Effectiveness of risk minimization
1) To characterise utilization patterns of strontium ranelate
2) To estimate the prevalence of contraindications in SR users during the period before and after the May 2013 DHPC.
Safety
3) To estimate the incidence rates of cardiac and thromboembolic events in SR users with and without contra-indications prior and after May 2013 DHPC
4) To compare the risk of cardiac and thromboembolic events between new users of SR and new users of oral bisphosphonates without contra-indications, both before and after the May 2013 DHPC.

Study design
Multi-national multi-database approach with:
1. Population-based cohort study
2. Nested case control analysis in a cohort of new users of strontium ranelate or oral bisphosphonates (BP)

Population Setting
The study will be conducted using routinely collected health care data from databases that participate in the EU-ADR Alliance. EU-ADR Alliance is a network of research institutes that conduct pharmacoepidemiological research. For this study data will be used from 5 EU countries: Denmark, Italy, the Netherlands, Spain, and the United Kingdom.

Study population
The study population will comprise the entire source population for the measurement of risk minimization effectiveness. It comprises a cohort of new SR and oral bisphosphonate users for the comparative safety study. Specific inclusion and exclusion criteria will apply

Patients with uncontrolled asthma or severe asthma are at increased risk of severe asthma exacerbation. Severe asthma exacerbation is associated with considerable morbidity and premature death. There are few real life data on the incidence of severe asthma exacerbation; and data on asthma-related mortality, because of low numbers, is even more rare. With this study, using data from six European large electronic health care databases, we want to i) study the rate of severe asthma exacerbations (both in asthma and severe asthma patients), ii) study the mortality rate in patients with severe asthma and iii) study the asthma-related mortality rates associated with an asthma exacerbation in patients with severe asthma. A retrospective cohort study will be conducted including patients aged 5 years or older and diagnosed with asthma, using multi-national, multi-databases from six European electronic health care databases from the Netherlands, Italy, United Kingdom (UK), Denmark and Spain. The study period runs from 2008 until 2013. The study population will consist of all patients, 5 years or older, present in the respective databases for at least 1 year, and diagnosed with asthma. The primary endpoints consist of severe asthma exacerbation and death. Severe asthma exacerbation is defined as need of systemic corticosteroids, OR hospital visit (ER or admission), all for reasons of asthma exacerbation. Death will be assessed either from the demography table or based on death specific disease codes. Where available, cause of death will be evaluated and classified as ?asthma? or? non-asthma? related. Data from six electronic health care databases from Europe will be used, namely the Integrated Primary Care Information Project (IPCI) from the Netherlands, the Sistema d’Informació per al Desenvolupament de la Investigació en Atenció Primària (SIDIAP) from Spain, Clinical Practice Research Datalink (CPRD) from the UK, Aarhus (Denmark), and the Health Search CSD Longitudinal Patient Database (HSD) and Pedianet database, both from Italy. Descriptive statistics will be used. Categorical data will be presented as counts (n) and proportions (%) along with (95% confidence intervals). For continuous data, the number of observations (n), mean, standard deviation, median (with interquartile range) will be presented. The incidence rate of severe asthma exacerbation will be calculated by dividing the numerator (number of severe asthma exacerbations) by the total number of years of follow-up. Differences in incidence rate (by gender, age, country, calendar year) will be tested using Poisson Regression. Asthma-related mortality will be assessed in a predefined time window (15, 30, 45 – 60 days) upon severe asthma exacerbation. In addition, a pooled analysis will be conducted, pooling the data from the different databases. The first report will provide details on the incidence rate of severe asthma exacerbations in patients with asthma and in patients with severe asthma. This first report will also provide the number of patients who died during follow-up. The second report (if number of patients who died is high enough) will provide asthma-related mortality rates.

Objectives: To describe the drug treatment patterns followed by type 2 diabetes mellitus (T2DM) patients in real life conditions in 5 European countries (France, Italy, Spain, The Netherlands and UK). Study Design: Retrospective observational database study in the Health Improvement Network in the UK (THIN-UK), the Echantillon Généraliste de Bénéficiaires in France (EGB-FR), the Sistema d’ Informació per al Desenvolupament de la Investigació en Atenció Primària in Spain (SIDIAP-SP), the Health Search Longitudinal Patient Database in Italy (HSD-IT), and the PHARMO Institute Database Network in The Netherlands (PHARMO-NL).This study consists of 3 phases: Phase I: Drug treatment patterns followed by T2DM patients in real-life conditions Phase II: Patient characteristics at treatment changes and occurrence of macrovascular events during follow-up Phase III: Health care resource utilization associated with T2DM To expedite the execution of the study, the protocol has been split in two: the current protocol only deals with phase I, and another protocol for phase II and III will follow within 2 months, when definitions can be aligned between the databases. Study Population: Adult T2DM patients will be identified for possible inclusion in the study using a proxy of having at least two consecutive prescriptions/drug dispensings of oral antidiabetic drugs (OAD) within a 6 month period at any time in the available medication records, or a diagnosis of type 2 diabetes. Patients with less than 12 months of continuous enrollment, with a registered diagnosis of type 1 diabetes or gestational diabetes will be excluded. Data Collection Methods: This study will use the information collected in the THIN, SIDIAP, HSD, PHARMO and EGB databases. The first 4 contain primary care records and the last one is an administrative claims database (see description of databases in section 3.3). Data Analyses: PHARMO will provide to other participating databases a validated tool that will process prescription records to describe treatment changes to create patient flows within a predefined study period in a standardized manner. This tool will generate a dataset with all treatment change dates, combinations of drugs used before and after the change, sequential change numbers and lines of treatment according to the combination of drug classes as defined in this protocol. From this dataset Burt tables will be generated for consecutive treatment changes to describe proportions of the population changing from one treatment to another (drug level, drug class level and level of line of treatment). These data will be summarized in flow diagrams describing consecutive changes and new lines of treatment. PHARMO will collate these data in a study report. The generated dataset containing the changes in the lines of treatment will also serve as a starting point for further analyses in phases II and III. Sample Size/Power: All patients meeting the inclusion and exclusion criteria will be included in the analysis. This is a descriptive study and therefore no power calculations will be performed. Limitations/Strengths: A limitation of this study is that primary care patient records and administrative claims data are not collected for research purposes and may not be complete: primary care databases may be missing prescriptions prescribed by specialists, and administrative claims are recorded by physicians to support reimbursement, and may not reflect medication that is not reimbursed. Another limitation of this study is that it is mainly compromised of primary care medical records databases with limited prescription data (mainly drug prescription and prescription date), it is not possible to define prescription duration or treatment episodes and thus a disputable period of 9 months was elected to precisely identify treatment continuation / discontinuation. Although this period has been justified according to clinical practice it will in some cases incorrectly define patients that continue or discontinue treatment. A note that should be made is that eligible patients will be identified for possible inclusion in the study using a proxy of having at least two consecutive prescriptions/drug dispensings of OADs within a 6 month period at any time in the available medication records, those patients receiving OADs for other diseases different from T2DM will be improperly included in the study as unfortunately not all patients will have a diagnostic code for T2DM recorded in the database. However, the number of patients receiving the OADs for other diseases is expected to be low, as well as the number of patients with a diagnostic code for T2DM and no two consecutive OADs. A strength of this study is the ability to access a large number of patients representative for diabetes populations in several European countries in a real-world setting. Another strength is the fact that all datasets are processed using the same tool to ensure homogeneity of the analyses.