Our knowledge of a drug’s potential for harm is incomplete at the time of drug licensing leaving residual questions about the long-term safety and effectiveness of drugs in the ‘real world’. Pharmacoepidemiologic research can contribute to the study of the unintended effects of drugs. The central aims of this dissertation were to create new knowledge about drug-related harm in the postmarketing environment using pharmacoepidemiologic methods and larged linked databases, and understand how various types of design and analytic strategies can be applied to reduce bias and threats to internal validity when studying drug harm. The aims of the thesis were achieved by performing three studies. The first study examined elderly individuals hospitalized with bradycardia and identified an association with recent initiation of cholinesterase inhibitor therapy (adjusted odds-ratio 2.13, 95% confidence interval 1.29 to 3.51). The second study examined the measurement properties of administrative diagnostic codes for subtrochanteric and femoral shaft fractures and found the positive predictive value and sensitivity of the codes to be reasonably good (90% and 81%, respectively). This study was linked to the third study which explored the association between long-term bisphosphonate use and subtrochanteric or femoral shaft fractures in postmenopausal women and found an increased risk of these unusual fractures in women with greater than 5 years of bisphosphonate use. The research performed as part of this thesis provides an example of the types of new knowledge about drug-related harm that can be generated using pharmacoepidemiologic designs and analytic strategies. The pharmacoepidemiologic studies will play an important and dynamic role in the larger evolving focus on post-marketing drug safety and effectiveness as new data sources become increasingly available and and the methods within the pharmacoepidemiologic discipline become more sophisticated and refined.

In recent years, many countries have struggled with the fact that expenditures on health care are growing much faster than the overall level of wealth. Research objectives: 1) to conduct a meta-analysis of heparins by the means of their efficacy, safety parameters and treatment outcomes; 2) to conduct pharmacoepidemiological assessment of long-term heparins utilization in Lithuania; 3) to develop a pharmacoeconomic cost-minimization model for low-molecular-weight heparins based on reference pricing methodology; 4) to investigate heparins prescribing trends and to evaluate heparins prescription adherence to international clinical guidelines at a secondary level clinical hospital. Meta-analysis results showed that low-molecular-weight heparins could be considered interchangeable due to similar therapeutic profiles in some indications. In Lithuania consumption of heparins and corresponding costs were constantly increasing during the period of investigation; therefore it would be relevant to implement modern pharmacoeconomic methodologies to regulate costs. Cost-minimization model suggested that expenditures on this group of medicines could be decreased by nearly 70 percent. Analysis of pharmacoepidemiological study data confirmed that heparins prescription practices at the clinical hospital were insufficiently regulated. In addition this study conducted at the clinical hospital revealed non-compliance of heparins safety monitoring practices with clinical guidelines. / Pastaraisiais metais daugelyje šalių sveikatos priežiūros išlaidos augo daug greičiau nei bendras gerovės lygis, todėl yra nuolat diskutuojama, kaip šį išlaidų augimą reikėtų kontroliuoti. Darbo uždaviniai: 1) atlikti heparinų preparatų meta-analizę, palyginant jų efektyvumo ir saugumo parametrus bei gydymo baigtis; 2) atlikti heparinų preparatų ilgalaikio suvartojimo Lietuvoje farmakoepidemiologinį tyrimą; 3) suformuluoti farmakoekonominį kaštų mažinimo sprendimų modelį mažos molekulinės masės heparinų preparatų grupei, remiantis referentinės kainos metodika; 4) ištirti heparinų preparatų skyrimo tendencijas antrinio lygio klinikinėje ligoninėje ir palyginti heparinų preparatų skyrimo atitikimą tarptautinėms gairėms. Meta-analizės rezultatai parodė, jog mažos molekulinės masės heparinai gali būti tarpusavyje pa¬keičiami dėl analogiškų terapinių savybių tam tikrose indikacijose. Heparinų preparatų suvartojimas ir atitinkamos išlaidos tiriamuoju laikotarpiu Lietuvoje nuolat didėjo, todėl būtų aktualu taikyti šiuolaikines farmakoekonomines išlaidų reguliavimo metodikas. Pritaikius kaštų mažinimo modelį heparinų preparatų grupei, būtų galima sumažinti išlaidas šios grupės preparatams beveik 70 procentų. Farmakoepidemiologinio tyrimo rezultatai atskleidė, jog heparinų preparatų skyrimo praktika klinikinėje ligoninėje buvo nepakankamai reglamentuota. Taip pat heparinų preparatų saugumo parametrų stebėjimo praktika ligoninėje neatitiko tarptautinių rekomendacijų.

Venous thromboembolism (VTE) which includes pulmonary embolism (PE), or deep venous thrombosis (DVT) poses an important disease burden, however, much remains unknown about the risk factors that cause it. In recent years, more attention has focused on medications that play a role in the development of drug-induced venous thrombosis. The three studies in this dissertation explore the risk of VTE in relation to the use of specific pharmacologic agents; glucocorticoids, 5ARIs and statins in three distinct patient populations with; asthma, benign prostatic hyperplasia (BPH) and hypercholesterolemia, using different approaches to address the inevitable confounding present in etiologic pharmacoepidemiologic research. Using a nested case-control design for the first two studies and cohort design for the last, we assessed the risk of VTE in relation to timing of drug exposure, duration of use, number, and dose of prescriptions. The base populations comprised subjects who received at least one prescription for any of the pharmacologic agents of interest (during 1995–2015 for study 1 and 2 and 1995–2018 for study 3) in the UK-based Clinical Practice Research Datalink. We used descriptive analyses as well as conditional logistic regression and Poisson regression models to evaluate the relationship between these drugs and the risk of VTE. Study 1 examined the relationship between glucocorticoid use and venous thromboembolism among asthma patients age 20–59. We found that current and systemic glucocorticoid use was associated with an increased risk of VTE, with a dose-response relationship. Study 2 explored the relationship between VTE and 5ARI use compared to alpha blocker use among patients, age 40–79, with BPH. We observed that cumulatively high doses of 5ARI+/-AB increases the risk of incident VTE. In study 3, we examined the relationship between VTE and statin use compared to fibrate use among 40–79-year-old patients with hypercholesterolemia. We observed that statin use decreases the risk of incident VTE. These three studies in a large population-based database of high quality, efficiently evaluate the safety/unintended benefit of glucocorticoids, 5ARIS and statins, with the hope to guide the development of guidelines for their use in prolonged care of asthma, BPH and hypercholesterolemia, respectively. / 2023-08-25T00:00:00Z

Indiana University-Purdue University Indianapolis (IUPUI) / Polypharmacy leads to increased risk of drug-drug interactions (DDI’s). In this dissertation, we create a database for quantifying fraction of metabolism (fm) of CYP450 isozymes for FDA approved drugs. A reproducible data collection protocol was developed to extract key information from publicly available in vitro selective CYP enzyme inhibition studies. The fm was then estimated from the curated data. Then, proposed a random control selection approach for nested case-control design for electronical health records (HER) and electronical medical records (EMR) databases. By relaxing the matching by case’s index time restriction, random control dramatically reduces the computational burden compared with traditional control selection approaches. Using the Observational Medical Outcomes Partnership gold standard and an EMR database, random control is demonstrated to have better performances as well. Finally, combining epidemiological studies and pharmacokinetic modeling with fm database, we detected and evaluated high-dimensional drug-drug interactions among thirty high frequency drugs. Multi-drug combinations that increased risk of myopathy were identified in the FAERS and EMR databases by a mixture drug-count response model (MDCM) model. Twenty-eight 3-way and 43 4-way DDI’s increased ratio of area under plasma concentration–time curve (AUCR) >2-fold and had significant myopathy risk in both databases. The predicted AUCR of omeprazole in the presence of fluconazole and clonidine was 9.35; and increased risk of myopathy was 6.41 (LFDR = 0.002) in FAERS and 18.46 (LFDR = 0.005) in EMR. We demonstrate that combining health record informatics and pharmacokinetic modeling is a powerful translational approach to detect high-dimensional DDI’s. / 2 years

Urinary incontinence, one of the most prevalent conditions in elderly living in nursing homes (NH) was shown to significantly impact patient's quality of life (QOL) and health outcomes. Bladder antimuscarinics (BAM), the main drug class to treat urinary incontinence, have limited effects in managing the condition; however, given their anticholinergic properties and the characteristics of those living in NH, BAM could potentially lead to serious health consequences in this population. We conducted a retrospective cohort study with a new-users design by linking existing Veterans Affairs (VA) data (inpatient, outpatient, pharmacy administrative files, and Minimum Data Set- MDS) between fiscal years 2003 and 2009. Potential risks (i.e. fractures and negative impact on cognitive performance) and benefits (i.e. improvement in urinary incontinence, social engagement and overall QOL) associated with initiation of a BAM were assessed in elderly (65+) admitted for long-term care in the VA Community Living Centers. Descriptive statistics were used to compare BAM new-users and non-users at baseline; in addition, logistic regression was used to identify important predictors of BAM initiation. Treatment selection bias was addressed by using the propensity score matching method. After balancing the groups on baseline characteristics, the risk of fractures (hip fracture, any fracture) in relationship with BAM initiation was evaluated using Cox proportional hazard analysis. BAM impact on the cognitive status measured by the MDS-Cognitive Performance Scale (CPS) was evaluated through generalized estimated equations (GEE) method. Similarly, possible benefits measured through MDS were assessed via GEE. The final cohort included 1195 BAM new-users (with the majority being prescribed Oxybutynin immediate-release) and 22,987 non-users. Predictors of BAM initiation included demographic characteristics, bladder and bowel continence status, comorbidities, medication use, cognitive performance and functional status. Our study showed that BAM improved urinary continence (OR=1.27, 95%CI: 1.07-1.50) in those treated; social engagement as measured by MDS-Index of Social Engagement also improved in users, although at a level that is not clinically significant (difference in mean MDS-ISE=0.2074, 95%CI: 0.0550-0.3598). However, BAM initiation increased the risk of fractures (hip: HR=3.69, 95% CI: 1.46 - 9.34, p=0.0059; any fracture: HR=2.64. 95% CI: 1.37 - 5.10, p=0.0039). Our results showed no difference between new-users and non-users with regard to mean CPS and overall QOL. The purpose of the study was to clarify the proper role of medication use in the management of urinary incontinence in elderly in the VA CLC. The results raise questions about the continued use of Oxybutynin IR, the main BAM prescribed in this population. Given the increased risk for fractures in the context of potential improvement in urinary continence with no clinically significant improvement in social engagement, a wiser step might be to investigate the safety profile for newer BAM for situations when an addition to non-pharmacologic management for urinary incontinence is desired for elderly in long-term care.

Statins are cholesterol-lowering medications with immunologic properties. To assess the role of statins on incident immune-mediated conditions, a modified case-cohort study was performed using administrative databases from the Midwest Veterans Administration (VA) region. A comparison sub-cohort was formed by randomly sampling 10,000 subjects with medical and pharmacy benefits during fiscal year (FY) 2002. Cases were identified by inpatient or outpatient medical claims using International Classification of Disease, Ninth Revision (ICD-9) codes between FY 2003-2004. All subjects needed at least one year of medical claims and at least one pharmacy claim. The incident cases (n=28,642) included non-mutually exclusive groups of immune-mediated (n=2,327), infectious (n=8,221), and non-immunologic (n=10,730) diagnoses. Demographic and medical variables were obtained from FY 2001-2004, and pharmacologic data from FY 2002-2004. Cox proportional hazards regression modeling was used to estimate hazard ratios for the current statin use (within the last 180 days) and former statin use, compared to non-users, including time-dependant variables for demographic factors, comorbidity as measured by Elixhauser and Chronic Disease Score variables, medications, and visit rates after initiating statins. Current statin use was associated with decreased diagnoses rates of psoriasis; rheumatoid arthritis; inflammatory bowel diseases, including ulcerative colitis and Crohn disease; diffuse connective tissue diseases, including systemic lupus erythematosus; ankylosing spondylitis; bacterial pneumonia; urinary tract infection; cellulitis; sepsis; candidiasis; osteomyelitis; and tuberculosis. Former statin use was also associated with increased rates of polymyalgia rheumatica, sepsis, and osteomyelitis. Statin use was not associated with other spondylitis, multiple sclerosis, thyroiditis, sarcoidosis, temporal arteritis, influenza, shingles, histoplasmosis, or pyelonephritis. Although current statin use appeared protective for some study conditions, selection bias, misclassification, healthy user effects, adherence bias, confounding by indication, and surveillance bias were considered as possible explanations of the study findings.

Objective: To compare statins according to the pharmacokinetic and pharmacodynamic characteristics within the drug class and to perform the comprehensive analysis of statins consumption in Lithuania between 2005 and 2007 years. Methods: MEDLINE database was searched to identify and evaluate all literature relating to pharmacokinetic and pharmacodynamic chareacteristics of statins. The statins sales data on units and wholesale prices in all Lithuanian regions over three years (2005 – 2007) were obtained from SoftDent, JSC database. Drugs were classified according to the Anatomic Therapeutic Chemical system and use was quantified in terms of defined daily doses. The consumption of statins was calculated by DDD methodology and expressed as DDD per 1.000 inhabitants per day. Expenditures were calculated using retail drug costs noted in basic price catalogue for reimbursement medicines, for each year separately. Pharmacoeconomic calculations were done according to cost minimization and reference price methodologies. Results: According to meta-analysis, Nice (2006 years) recommendations and clinical trials data statins are therapeutically equivalent medicines. The total consumption of these drugs increased from 3.9 DDD/1000 inhabitants/day in 2005 and reached the value 8.4 DDD/1000 inhabitants/day in 2007 in Lithuania, so the total consumption of statins increased by 53.6% over three years (2005 – 2007) period. Comparing with statins consumption in other countries, this meaning... [to full text] / Tikslai: Šio darbo tikslas yra palyginti statinus tarpusavyje pagal farmakokinetines ir farmakodinamines savybes bei atlikti statinų suvartojimo Lietuvoje analizę 2005 – 2007 metais. Metodai: Duomenys apie statinų farmakokinetines ir farmakodinamines savybes buvo surinkti iš MEDLINE elektroninių duomenų šaltinių. Duomenys apie statinų pardavimus vienetais ir didmeninėmis kainomis Lietuvoje per 2005 – 2007 metus gauti iš UAB SoftDent duomenų bazės. Vaistai buvo suklasifikuoti pagal anatominę terapinę cheminę (ATC) klasifikaciją. Statinų suvartojimas buvo vertinamas pagal apibrėžtos dienos dozės (DDD – daily defined dose) metodiką, o duomenys įvertinti pagal DDD skaičių, tenkantį 1000 gyventojų per vieną dieną. Išlaidos statinams buvo suskaičiuotos mažmeninėmis kainomis, remiantis kiekvienų metų kompensuojamųjų vaistų bazinių kainų kainynu. Statinų farmakoekonominei analizei atlikti buvo taikytas kainų mažinimo bei referentinės kainos nustatymo principas. Rezultatai: Remiantis metaanalizių, Nice (2006 metų) rekomendacijų ir klinikinių tyrimų duomenimis galima teigti, kad statinai prilygsta vienas kitam klinikiniu poveikiu. Bendras statinų suvartojimas padidėjo nuo 3,9 DDD/tūkstančiui gyventojų/dieną 2005 metais iki 8,4 DDD/tūkstančiui gyventojų/dieną 2007metais, taigi, per trejus metus bendras šių vaistų suvartojimas išaugo 53,6%. Palyginus su kitų šalių duomenimis, statinų suvartojimas 2007 metais Lietuvoje buvo apie 20 kartų mažesnis. Išlaidos statinams per trejus metus ( 2... [toliau žr. visą tekstą]

FundaÃÃo de Amparo à Pesquisa do Estado do Cearà / CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / A escassez de medicamentos adequados ao uso pediÃtrico obriga os prescritores a extrapolarem informaÃÃes obtidas atravÃs de testes com indivÃduos adultos para crianÃas, bem como a adaptarem formulaÃÃes desenvolvidas para adultos. Os riscos sÃo elevados podendo comprometer a eficÃcia e a seguranÃa dos tratamentos.Conhecer a problemÃtica da carÃncia de formulaÃÃes farmacÃuticas adequadas ao uso em crianÃas e suas repercussÃes prÃticas em um hospital pediÃtrico do SUS. Estudo descritivo transversal, envolvendo: busca na literatura internacional de medicamentos cuja forma ou formulaÃÃo representam um problema para o uso em crianÃas (MP, medicamentos problema) e identificaÃÃo desses medicamentos no mercado farmacÃutico brasileiro; inquÃrito com mÃdicos de um hospital pediÃtrico (N=48, 98% do total) sobre quais sÃo os MP em sua prÃtica clÃnica e seguimento da prescriÃÃo e preparo de MP sÃlidos na instituiÃÃo. Foi empregada a ClassificaÃÃo AnatÃmica TerapÃutica e QuÃmica de medicamentos e cÃlculo de freqÃÃncias das variÃveis. O projeto foi aprovado pela comissÃo de Ãtica da instituiÃÃo. Foram identificados 131 MPI (medicamentos problema internacionais), 105 destes sÃo comercializados no Brasil, sendo 85 de uso pediÃtrico. Os princÃpios ativos mais freqÃentes foram: salbutamol, furosemida, paracetamol, cisaprida e morfina. Os MP mais citados pelos mÃdicos foram captopril, furosemida, digoxina, espironolactona, hidroclorotiazida e prednisona. A carÃncia de preparaÃÃes orais, parenterais e em baixas doses foram os problemas mais citados. Foi acompanhada a adaptaÃÃo de 24 distintos MP sÃlidos (89 prescriÃÃes). Todas as prescriÃÃes apresentavam inconformidades, bem como todos os procedimentos de preparo. As doses administradas foram 3,47 a 1.125% do preconizado (22,7% inferiores e 39.5% superiores); somente em 37,8% dos casos foi administrada a dose preconizada. A carÃncia de preparaÃÃes apropriadas para uso em crianÃas à um problema em todo o mundo. No Brasil isso à agravado pela falta de condiÃÃes adequadas para a adaptaÃÃo de formulaÃÃes em hospitais, bem como pela inobservÃncia de procedimentos padronizados. / The scarcity of medicines developed to be used in children creates the need of to extrapolate information obtained by tests in adults and of to adapt adult formulations to this age group. The risks are great and can compromise the efficacy and safety of treatments.To know the problem of lack of formulations apropriated to be used in children and its practical repercussions in a SUS pediatric hospital.A cross-sectional, descriptive study, involving: literature search for medicaments whose formulations represents a problem for use in children (Medicine Problem â MP) and the identification of these medicines on the Brazilian market; a survey applied to doctors in a pediatric hospital to know which are the PM in their clinical practice; follow up of prescription and adaptation of solid PM in this institution. The Anatomic Therapeutic Chemical classification of medicines was adopted; the frequencies of variables were calculated; the project was approved by the hospital Ethics Committee.A total of 131 IPM (International Problem Medicine) were identified, 105 of these are marketed in Brazil, including 85 pediatric preparations. The most frequent MP were salbutamol, furosemide, paracetamol, cisaprida and morphine; The doctors (N=48, 98% of total) referred mainly captopril, furosemide, digoxine, espironolactone, hidroclorotiazide e prednisone as PM. Lack of oral, parenteral, or lower doses formulations were the more frequent problems. The preparation of 89 solid PM was followed up; there were inadequacies in all prescriptions and preparing procedures. The final dosis administered were 3,47 to 1.125% of expected (22,7% under and 39 over); only 37,8 of children received the standardized dosis. The lack of appropriate preparations to be used in children is a problem all over the world. In Brazil this problem is aggravated by the lack of adequate conditions in hospitals to adapt formulations and poor compliance with standard procedures.

CoordenaÃÃo de AperfeiÃoamento de NÃvel Superior / CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / INTRODUÃÃO: A populaÃÃo pediÃtrica se ressente dos poucos estudos que relacionem o perfil de utilizaÃÃo e ocorrÃncia de reaÃÃo adversa a medicamentos (RAM) em crianÃas hospitalizadas. OBJETIVOS: Descrever e avaliar a utilizaÃÃo de medicamentos e a ocorrÃncia de reaÃÃes adversas em pacientes pediÃtricos internados no Hospital Infantil Albert Sabin na perspectiva de contribuir para a reduÃÃo dos agravos decorrentes do uso de medicamentos em crianÃas hospitalizadas. METODOLOGIA: Estudo observacional longitudinal prospectivo, de seguimento de pacientes pediÃtricos hospitalizados por mais de 24 horas, em um hospital pÃblico de referÃncia. Pacientes de 1-173 meses de idade foram incluÃdos no estudo no perÃodo de 01 de agosto a 31 de dezembro de 2001. Foram realizadas visitas diÃrias à enfermaria para inclusÃo ou acompanhamento de pacientes; entrevistas com as mÃes por meio de um questionÃrio estruturado para levantar caracterÃsticas sÃcio demogrÃficas e antecedentes patolÃgicos dos entrevistados, familiares e das crianÃas, revisÃo das prescriÃÃes e dos prontuÃrios, conversa com mÃdicos, enfermeiras e farmacÃuticos quando necessÃrio. As suspeitas de RAM foram avaliadas pelo CEFACE conforme a metodologia recomendada pelo Programa de FarmacovigilÃncia da OMS. Na anÃlise estatÃstica foram utilizados o teste exato de Fisher, Student (t) e wilcoxon, considerando-se o nÃvel de significÃncia p < 0,05. RESULTADOS: Durante o perÃodo de estudo ocorreram 272 admissÃes predominantemente de crianÃas entre 1 e 23 meses de idade (47,4%); com mÃes de 1o grau completo ou incompleto de escolaridade (70,6%); famÃlias de renda familiar entre 1 e 5 salÃrios mÃnimos (61,0%). Dentre as crianÃas admitidas, 265 foram expostas a medicamentos no hospital (97%), recebendo em mÃdia 6,4 (1-18) medicamentos; a mÃdia de permanÃncia hospitalar foi de 14,7 (2-67) dias. O diagnÃstico mais freqÃente foi pneumonia (30%), a classe terapÃutica mais prescrita foi Antiinfecciosos de Uso SistÃmico (25,9%). Foram detectados 420 eventos adversos; destes, 33 foram classificados como RAM. A incidÃncia acumulada de RAM foi 12,5% (33/265) e a densidade de incidÃncia 0,8% (33/4042 pacientes-dia monitorizados). A pele foi o ÃrgÃo mais afetado (48,9%). O grupo terapÃutico mais implicado foi Antiinfecciosos de Uso SistÃmico (53,2%). As RAM foram leves ou moderadas em 97,9% dos casos, 57,5% ProvÃveis e a maioria foi dose independente (55,3%). Na anÃlise multivariada as chances de uma crianÃa hospitalizada apresentar uma RAM cresceram com o nÃmero de medicamentos administrados, entre aqueles do sexo masculino, com menor idade (< 2anos) e internada anteriormente de 3 a 4 vezes. CONCLUSÃO: Foi significativa a proporÃÃo de crianÃas menores de 2 anos usando medicamentos. A predominÃncia do uso de antimicrobianos à esperado e determina o perfil de RAM detectados. A identificaÃÃo de fatores de risco associado a RAM possibilita a seleÃÃo de subgrupos de pacientes pediÃtricos que requereriam maior racionalizaÃÃo terapÃutica e avaliaÃÃo da seguranÃa de medicamentos. PALAVRAS-CHAVE: farmacoepidemiologia; medicamentos; pediatria.

L’objectif de ce travail est de présenter et évaluer une nouvelle méthode, PGRx,systématique cas-référents en pharmaco-épidémiologie avec son application à l’étudede l’infarctus du myocarde (IDM). Elle se distingue par la collecte systématique etcontinue de cas d’événements dans des centres spécialisés et d’un pool de référenceen médecine générale dont sont tirés les témoins appariés aux cas. L’évaluation durisque d’IDM associé au diclofénac (OR 1.5) et celle du bénéfice associé aux statines(OR 0.75) montrent des résultats similaires à ceux publiés (respectivement OR 1.4 etOR 0.74). Nous montrons que les référents sont un échantillon représentatif de lapopulation française en termes de motif de consultation et valide en termesd’évaluation de facteurs de risque. La concordance entre la mesure de l’exposition parla déclaration du patient et par les prescriptions médicales est excellente pour lesmédicaments cardiovasculaires (95%). Notre travail sur une série d’études montre quela collecte systématique de cas et d’un pool de référence, selon la méthode PGRx, estfaisable, reproductible et valide en termes de résultats et d’indicateurs de qualité. / The objective of this work is to present and assess PGRx, a new systematic case-referentsmethod in pharmacoepidemiology and its application on the study of themyocardial infarction (MI). The originality of PGRx is the systematic and on-goingcollect of cases of events in a network of specialized centres and of a pool of referentsin general practice (GP), from which controls are selected by matching to the cases.The assessment of the risk of MI associated with diclofenac (OR 1.5) and of thebenefit on MI associated with statins (OR 0.75) displays similar results than theliterature (respectively OR 1.4 and OR 0.74).We show that the pool of referents is arepresentative sample of the French population in terms of reasons of consulting a GPand valid in terms of risk factors’assessment. Agreement between the measure ofexposure from patients’ self-report and from physician’s report of their prescriptionsis excellent on cardiovascular drugs (95%). Our work, through several studies, showsthat the systematic collect of cases and of a reference pool by the PGRx method isfeasible, reproducible and valid in terms of results and quality indicators.