“La malaltia renal crònica (MRC) engloba un conjunt de malalties i implica la presència d’alteració estructural o de la funció renal. És un problema important de salut pública i s’estima la seva prevalença en el nostre medi d’entre el 7 i 15%. El seu maneig es dur a terme principalment en atenció primaria i el seu objectiu és prevenir i alentir la progressió d’aquesta malaltia tot reduint el risc de malaltia cardiovascular i de complicacions associades. Es basa en mesures higiènico-dietètiques i el tractament farmacològic dels factors de progressió de la MRC i del risc cardiovascular, com també del risc de complicacions de la malaltia.
El tractament dels factors de risc per la MRC inclou el maneig de la hipertensió arterial (HTA), la diabetis mellitus (DM), la dislipèmia (DLP), la hiperuricèmia, l’anèmia, l’obesitat, el virus de l’hepatitis C (VHC), les alteracions del metabolisme ossi i mineral (hormona paratiroidea i la hiperfosfatèmia), la hiperpotassèmia, l’acidosi metabòlica i les complicacions trombòtiques com l’ictus cardioembòlic.
Atès que la MRC és un problema sanitari molt important cal disposar d’informació per conèixer les pràctiques clíniques existents en relació amb el tractament de la MRC a Catalunya i per identificar possibles àrees de millora en el maneig terapèutic de la malaltia.
L’objectiu principal de l’estudi és descriure les característiques i la utilització dels diferents tractaments farmacològics de la població de pacients amb MRC de Catalunya. Com a objectius secundaris es pretén descriure les característiques sociodemogràfiques, clíniques i comorbiditats de la població amb MRC; Descriure la utilització del tractament farmacològic de la població diagnosticada de MRC segons les comorbiditats més importants (HTA, DM tipus 2 i malaltia nefrològica); Descriure la utilització del tractament farmacològic de la població amb MRC segons FG i finalment analitzar la utilització dels fàrmacs segons albuminúria.
Per fer-ho es realitzarà un estudi de cohorts que inclou pacients amb MRC entre en el període de 2018-2022.”

La migranya és un trastorn neurològic que afecta a un 15% de la població adulta, sent la setena malaltia més prevalent al món. És una cefalea primària que es caracteritza per episodis de dolor al cap d’entre 4 i 72 hores de durada.
Per al tractament simptomàtic agut de la migranya habitualment s’utilitzen antiinflamatoris no esteroidals, paracetamol, metamizol, triptans i derivats ergòtics. En 2022 s’han autoritzat dos nous fàrmacs, rimegepant i lasmiditan.
En canvi, per al tractament preventiu s’utilitzen propranolol, metoprolol, flunarizina, amitriptilina, topiramat, toxina botulínica A, a més d’altres fàrmacs amb evidència demostrada però sense indicació terapèutica com àcid valproic, candestartan, lisinopril i venlafaxina. En els últims anys s’han comercialitzat els anticossos monoclonals bloquejadors del pèptid relacionat amb el gen de la calcitonina (CGRP) o del seu receptor.

La migranya és un trastorn neurològic que afecta a un 15% de la població adulta, sent la setena malaltia més prevalent al món. És una cefalea primària que es caracteritza per episodis de dolor al cap d’entre 4 i 72 hores de durada.
Per al tractament simptomàtic agut de la migranya habitualment s’utilitzen antiinflamatoris no esteroidals, paracetamol, metamizol, triptans i derivats ergòtics. En 2022 s’han autoritzat dos nous fàrmacs, rimegepant i lasmiditan.
En canvi, per al tractament preventiu s’utilitzen propranolol, metoprolol, flunarizina, amitriptilina, topiramat, toxina botulínica A, a més d’altres fàrmacs amb evidència demostrada però sense indicació terapèutica com àcid valproic, candestartan, lisinopril i venlafaxina. En els últims anys s’han comercialitzat els anticossos monoclonals bloquejadors del pèptid relacionat amb el gen de la calcitonina (CGRP) o del seu receptor.

Els antagonistes de la vitamina K (AVK) i els anticoagulants orals directes (ACOD) poden interaccionar amb un gran nombre de fàrmacs per mecanismes farmacocinètics (FC) i/o farmacodinàmics (FD). Sovint, aquestes interaccions poden disminuir o augmentar l’efecte dels anticoagulants. En el cas d’un augment de l’efecte, poden acabar produint-se hemorràgies que poden arribar a ser greus i provocar l’ingrés hospitalari.
El nostre objectiu és analitzar quines hemorràgies de la nostra cohort de dades d’un estudi previ (2011-2020) poden haver estat ocasionades per interaccions FC i/o FD dels ACO amb altres tractaments concomitants. És per això que plantegem un estudi cas-control, on els casos seran tots els pacients que hagin patit alguna hemorràgia major durant el període d’estudi, per analitzar l’associació d’aquestes hemorràgies amb l’exposició concomitant d’ACO i altres fàrmacs que potencialment hi poden interaccionar.
Amb les dades que ja tenim disponibles (2011-2020) podem analitzar algunes de les interaccions dels ACO. Tanmateix, com que en aquella extracció no es van sol·licitar tots els fàrmacs que potencialment interaccionen amb ACO, es per això que necessitem afegir alguns grups farmacològics tant a prescripció com a facturació, i afegir la facturació d’alguns fàrmacs pels quals només havíem demanat prescripció.
Els fàrmacs que ja teníem a prescripció i ara necessitem facturació són:
• C01BD: Antiarítmics classe III (amiodarona, dronedarona)
• C08DA01: Verapamil
• C08DB01: Diltiazem
• C10AA: Estatines
• H02A, H02B: Corticoides sistèmics
• M01A: AINE
Els fàrmacs nous a afegir tant a prescripció com a facturació són:
• J01FA: Macròlids
• J01M: Quinolones
• J02AB, J02AC: Antifúngics
• L04AD01: Ciclosporina
• M04AA01: Al·lopurinol
• N02AX02, N02AJ13, N02AJ14: Tramadol
• N06A: Antidepressius

La insuficiència cardíaca (IC) es classifica habitualment segons la fracció d’ejecció del ventricle esquerre (FEVE), de manera que es diferencien tres fenotips; IC amb FEVE reduïda (IC-FEr), quan és = 40%, IC amb FEVE lleugerament reduïda o intermèdia (IC-FEIr), quan està entre 41-49%, i IC amb FEVE conservada (IC-FEc), si FEVE = 50%. També és habitual utilitzar la classificació funcional de la New York Heart Association (NYHA) per descriure el grau d’IC, basada en la gravetat dels símptomes.
L’objectiu del tractament de la IC és reduir la mortalitat, reduir el risc d’hospitalitzacions per descompensació de la malaltia i millorar la simptomatologia. El tractament farmacològic recomanat segons l’evidència científica varia segons el fenotip d’IC.
L’objectiu d’aquest estudi és classificar els pacients amb diagnòstic d’IC segons la FEVE i descriure les característiques clíniques i sociodemogràfiques d’aquestes persones diagnosticades d’IC i els tractaments farmacològics que s’utilitzen pel maneig de la malaltia.
Es portarà a terme un estudi de cohort amb la base de dades de SIDIAP que inclourà totes les persones amb diagnòstic d’IC a ECAP en el període de 2018 a 2022. Els pacients es classificaran segons la disponibilitat de registre de FEVE i de NYHA a ECAP, i es descriuran les seves característiques sociodemogràfiques i clíniques, a més del tractament farmacològic pel maneig de la IC.
Estem treballant en aquest estudi des de novembre de 2022 i ara sol·licitem les mateixes dades en format OMOP per replicar l’estudi.

Rationale and background: Paxlovid consists of nirmatrelvir (formerly PF-07321332), a potent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, co-administered with a low dose of ritonavir, which acts as a pharmacokinetic enhancer, orally twice a day for 5 days. Paxlovid is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults who do not require supplemental oxygen and who are at increased risk for progression to severe COVID-19.
The safety of Paxlovid in pregnant women is not known. The post-authorisation safety study (PASS) of Paxlovid in pregnant women is a regulatory commitment to the European Medicines Agency (EMA) and the United Kingdom (UK) Medicines and Healthcare products Regulatory Agency (MHRA).
Research question and objectives: The primary study objective is to estimate the birth prevalence, prevalence ratio, and prevalence difference of the following adverse pregnancy, offspring, and maternal outcomes in women with COVID-19 who are exposed to Paxlovid during pregnancy compared with those in women with COVID-19 who are exposed to molnupiravir (or other comparable medications for COVID-19), where available, during pregnancy or to women with COVID-19 unexposed to any study medications during pregnancy:
Pregnancy outcomes
• Spontaneous abortion
• Elective termination
• Stillbirth
• Preterm delivery
Offspring outcomes
• Major congenital malformations
• Intrauterine growth retardation/small for gestational age
Maternal outcomes
• Gestational diabetes
• Gestational hypertension
• Postpartum haemorrhage
• Maternal death
The secondary study objective is to assess maternal exploratory outcomes in outpatient and inpatient settings as available that will be identified based on conditions appearing in the study population after exposure to Paxlovid.
Study design: The study will focus on pregnant women. Within this population, there will be a descriptive analysis and comparative analyses. Molnupiravir, an antiviral with a similar recommended usage, will be used as an active comparator in the data sources in which it is available; other drugs may be incorporated as active comparators as more information becomes available. At the time of preparing this protocol, molnupiravir was not utilised or its use was not captured by some of the data sources (eg, France and Information System for Research in Primary Care [SIDIAP] in Catalonia, Spain). Therefore, a second comparator group is included in the study: individuals with COVID-19 unexposed to any study medication. Other medications to treat COVID-19 will be considered as active comparators in the future.
The study period will start on 01 January 2022 (in alignment with regulatory authorisation and launch in Europe) and end as late as possible.
Population: The target study population will be individuals with COVID-19 exposed to Paxlovid or comparator drug molnupiravir or other comparable medications and individuals unexposed to Paxlovid, molnupiravir, or other comparable medications (the unexposed comparison group), while they are pregnant.
Data sources: As of 20 September 2022, the MAH has confirmed that Paxlovid has been supplied to France, Germany, Italy, Spain, Slovenia, Sweden, and the UK, initially or continuing under special government contracts, resulting in different distribution and reimbursement channels being used and subsequent challenges capturing its prescription and distribution. Current information is that prescribed/dispensed Paxlovid should be captured in existing electronic population data sources in France, Spain, and the UK. The Italian Medicines Agency (AIFA) established a national registry for Paxlovid and other antivirals to treat COVID-19. At the time of this writing, capture of Paxlovid dispensing/prescriptions in the existing electronic data sources commonly used for pharmacoepidemiological research in Italy at this moment is expected to be minimal. As long as the German government continues to cover payments for Paxlovid, it is expected that Paxlovid prescriptions will not be captured in the German Statutory Health Insurance data sources.
The proposed data sources are the French Administrative Healthcare Database (SNDS), SIDIAP (Catalonia, Spain), and Clinical Practice Research Datalink–Aurum (CPRD Aurum) (UK). The UK OpenSAFELY data source and the AIFA patient registry will continue to be explored as potential supplementary data sources for this study.
Study size: All individuals meeting eligibility criteria during the study observation period will be included. As the summaries of product characteristics (SmPCs) recommend against use in pregnancy, Paxlovid exposure in this population is anticipated to be small.
Data analysis: Study data will be analysed as a cohort. Descriptive baseline characteristics will include tabulations of age, sex, comorbidities, selected concurrent medications, COVID-19 vaccination status, history of COVID-19, current COVID-19 status and setting of Paxlovid use (among Paxlovid users). Comparative analyses will be based on the estimation of risk/prevalence, risk/prevalence ratios, and risk/prevalence differences. Comparative analyses will control for measured confounding within each data source. Aggregated results from each data source will be combined using meta-analytic techniques as numbers allow. If a study population is too small, analyses will be only descriptive; pooling of results from various data sources will be undertaken only if at least 3 independent data points are available.

Study to be conducted with the ConcePTION common data model. We plan to extract the data for both Paxlovid protocols (pregnancy & liver_renal populations) in a unique extraction (one in 2024 for interim report 1, another in 2025-26 for interim 2 and final report), but we present two different application forms for each protocol endorsed by PRAC (EMA).
Paxlovid is dispensed in a specific circuit in Spain, not in the usual electronic prescription.

Rationale and background: Paxlovid consists of nirmatrelvir (formerly PF-07321332), a potent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protease inhibitor, co-administered with a low dose of ritonavir, which acts as a pharmacokinetic enhancer, orally twice a day for 5 days. Paxlovid is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults who do not require supplemental oxygen and who are at increased risk for progression to severe COVID-19.
The safety of Paxlovid in individuals with hepatic or renal impairment is not known. Assessing the safety of Paxlovid among individuals with moderate or severe hepatic or renal impairment is a regulatory commitment to the EMA.
Research question and objectives:
• What is the safety profile of Paxlovid in patients with COVID-19 and moderate or severe hepatic impairment?
• What is the safety profile of Paxlovid in patients with COVID-19 and moderate or severe renal impairment?
For the population of individuals with moderate or severe hepatic impairment, the objectives are:
Primary objectives
• To assess the safety of Paxlovid relative to the comparator populations prescribed molnupiravir (or other comparable medications for COVID-19), where available, and to unexposed patients with COVID-19.
• To assess side effects resulting from drug overexposure due to impaired liver function and with regard to severity and frequency compared with comparator groups. Safety outcomes for primary objectives are all safety events in outpatient and inpatient settings, as available, including the following safety outcomes of special interest:
• Hepatic transaminase elevations, clinical hepatitis, or jaundice
• Severe vomiting, nausea, diarrhoea, or abdominal pain
• Dysgeusia, headache, or hypertension
• Anaphylactic reactions
Secondary objective
• To assess all safety events included in the primary objective that require hospitalisation or emergency department visits
For the population of individuals with moderate or severe renal impairment, the objectives are:
Primary objectives
• To assess the safety of Paxlovid relative to the comparator population prescribed molnupiravir (or other comparable medications for COVID-19), where available, and to unexposed patients with COVID-19.
• To assess side effects resulting from drug overexposure due to impaired renal function and with regard to severity and frequency compared with comparator groups.
Safety outcomes for primary objectives are all safety events in outpatient and inpatient settings, as available, including the following safety outcomes of special interest:
• Severe vomiting, nausea, diarrhoea, or abdominal pain
• Dysgeusia, headache, or hypertension
• Anaphylactic reactions
Secondary objective
• To assess all safety events included in the primary objective that require hospitalisation or emergency department visits
Study design: The study will employ a cohort design and will make secondary use of multiple sources of data from electronic health records and/or claims data in European countries. Data sources currently selected have the ability to capture Paxlovid exposure where the target populations, study outcomes, and key covariates can be ascertained. The feasibility component of this research programme will provide counts of the target population, separately for Paxlovid users, users of molnupiravir, users of other comparable medications (Section 9.1.2, Table 2), and the unexposed comparator group. Relevant patient characteristics will be presented for each exposure group in the target population to allow an assessment of the feasibility of comparative analyses. Molnupiravir, an antiviral with a similar recommended usage, will be used as an active comparator in the data sources for which it is available; other drugs may be incorporated as active comparators as more information becomes available. At the time of preparing this protocol, molnupiravir was not utilised, or its use was not captured by some of the data sources (eg, France and Information System for Research in Primary Care [SIDIAP] in Catalonia, Spain). Therefore, a second comparator group is included in the study: individuals in the target populations with COVID-19 who had not received Paxlovid, molnupiravir or other comparable medications, referred to as “unexposed patients”. The study period will start on 01 January 2022 (in alignment with regulatory authorisation and launch in Europe) and end based on the calendar period coverage at the time of the last data extraction.
Population: The target study populations are individuals with moderate or severe hepatic or renal impairment with COVID-19 exposed to Paxlovid or comparator drug molnupiravir or other comparable medications, and individuals unexposed to Paxlovid, molnupiravir, or other comparable medications (the unexposed comparison group).
Data sources: As of 30 September 2022, the MAH has confirmed that Paxlovid has been supplied to France, Germany, Italy, Spain, Slovenia, Sweden, and the United Kingdom (UK), initially or continuing under special government contracts, resulting in different distribution and reimbursement channels being used and subsequent challenges capturing its prescription and distribution. Current information is that prescribed/dispensed Paxlovid should be captured in existing electronic population data sources in France, Spain, and the UK. The Italian Medicines Agency (AIFA) established a national registry for Paxlovid and other antivirals to treat COVID-19. At the time of this writing, capture of Paxlovid dispensing/prescriptions in the existing electronic data sources commonly used for pharmacoepidemiological research in Italy is expected to be minimal. As long as the German government continues to cover payments for Paxlovid, it is also expected that Paxlovid prescriptions will not be captured in the German Statutory Health Insurance data sources.
The proposed data sources for this study are the French Administrative Healthcare Database (SNDS), SIDIAP (Catalonia, Spain), and Clinical Practice Research Datalink Aurum (CPRD Aurum) (UK). The UK OpenSAFELY data source and the AIFA patient registry will continue to be explored as potential supplementary data sources for this study.
Study size: All individuals meeting eligibility criteria during the study observation period will be included. As the summaries of product characteristics (SmPCs) caution (EU) or contraindicate (UK) use in severe hepatic or renal impairment, Paxlovid exposure in these populations is anticipated to be small.
Data analysis: Study data will be analysed as a cohort. Descriptive baseline characteristics will include tabulations of age, sex, comorbidities, selected concurrent medications, COVID-19 vaccination status, history of COVID-19, current COVID-19 status and setting of Paxlovid use (among Paxlovid users). Comparative analyses will be based on the estimation of risk ratios and risk differences. Comparative analyses will control for measured confounding within each data source. Aggregated results from each data source will be combined using meta-analytic techniques as numbers allow. If a study population is too small, analyses will be only descriptive; pooling of results from various data sources will be undertaken only if at least 3 independent data points are available.

Study to be conducted with the ConcePTION common data model. We plan to extract the data for both Paxlovid protocols (pregnancy & liver_renal populations) in a unique extraction (one in 2024 for interim report 1, another in 2025-26 for interim 2 and final report), but we present two different application forms for each protocol endorsed by PRAC (EMA).
Paxlovid is dispensed in a specific circuit in Spain, not in the usual electronic prescription.

Rationale and background: The increasing use of medicines during pregnancy, coupled with a notable lack of safety information for a substantial portion of approved medicines, raises concerns regarding potential teratogenic and neurodevelopmental effects on the fetus. Certain medications with documented long-term teratogenic and neurodevelopmental effects on human fetuses have similarly demonstrated teratogenicity in animal studies. Such correlations emphasize the potential utility of embryo-fetal developmental toxicity (EFDT) studies in identifying medications with lasting effects on children after prenatal exposure. The Dutch National Institute for Public Health and the Environment (RIVM) and the Dutch Medicines Evaluation Board (CBG-MEB) compiled a database comprising rat and rabbit EFDT study outcomes, encompassing 198 European Union (EU) authorized human medicines. This database was used to rank medicines of increased concern, lower concern or minor concern based on malformations and/or embryo-fetal death (MEFL) and exposure safety margins compared to the maximum recommended human dose. In the ConcePTION project, we investigate the long-term effects on offspring after exposure to medications during pregnancy and lactation. Combining data from the animal studies and medication use prevalence data from pregnant women and women of childbearing age could help in prioritizing medicines that pose clinically relevant risk during pregnancy and facilitate the creation of a ranking list for future pharmaco-epidemiological studies.

Research question and objectives: What is the prevalence of prescriptions of medicines known to be associated with developmental toxicity in pregnant women and women of childbearing age?
Primary objectives:
1A. To determine the prevalence of medication use known to be associated with
developmental toxicity in pregnant women, by trimester of pregnancy.
1B. To determine the prevalence of medication use known to be associated with developmental
toxicity in women of childbearing age, by age of the women.
Secondary objective:
2A. To combine medication use prevalence data with pre-clinical data of rat and rabbit teratogens to make a ranking list of medicines known to be associated with developmental toxicity that have a high prevalence of prescription to humans.

Study design: A descriptive retrospective, multi-database cohort study will be conducted.

Population:
The target population will comprise all pregnant women and women of childbearing age registered in the participating data sources between 1 January 2015 – 31 December 2020. The index date for each pregnant women will be the start date of pregnancy. Follow-up continues until end of pregnancy (spontaneous or induced abortion, stillbirth or livebirth). Women of childbearing age will be followed each respective calendar year (2015 till 2020). The follow-up starts at 1 January and ends on 31 December or upon death, migration, becoming pregnant, performing sterilisation, or end of data availability, whichever occurs earliest.

Variables: The ConcePTION algorithm will be used to identify pregnancies. The primary outcome of interest is the prevalence of prescriptions of medicines known to be associated with developmental toxicity. All medicines use refers to prescribed or dispensed medicines as recorded in the participating data sources. All medicines will be identified by Anatomical Therapeutic Chemical (ATC) code. Pregnant women will be considered exposed to the medicines if they received at least one prescription during pregnancy. Women of childbearing age will be considered exposed to the medicines if they had received at least one prescription during follow-up.

Data sources: This study will include data from 4 national healthcare databases in 3 European countries (Italy, Spain, UK), pending feasibility and confirmation.
Study size: The study will include all pregnant women and women of childbearing age identified in the participating data source over a 5 years’ time span.

Data analysis: For objective 1, the prevalence of the medicines of interest will be computed for each data source stratified by trimester of pregnancy. Prevalence will be calculated per 1000 pregnancies with 95% confidence interval. To calculate the prevalence, the numerator will be the number of women having one or more prescription of the specific medicine within a given trimester. The denominator will be the number of women contributing to that trimester. For objective 2, the prevalence of the medicines of interest will be computed for each data source stratified by age. To calculate the prevalence, the numerator will be the number of women having one or more prescription of the specific individual medicines within the given study-period. The denominator will be the total number of women contributing at least one day of person-time to that study period. A sensitivity analysis with >1 prescription will be conducted in both cohorts.

We will use a previous data instance of the ConcePTION CDM, so no new data extraction is needed.