A vigilancia farmacológica no cenário brasileiro do sáculo 21 / Pharmacological surveillance in the Brazilian scenario of the 21st century / La vigilancia farmacológica en el escenario brasileño del siglo XXI

Resumo Os estudos em vigilancia farmacológica e ecofarmacológicas possibilitam o monitoramento, identificagao e minimi-zagao de efeitos nocivos advindos do uso de medicamentos. Diante disso, o presente estudo teve como objetivo descrever o cenário atual da farmacoepidemiologia e ecofarmacovigilancia no Brasil, no que se refere a produgao, registro, comerciali-zagao e uso de medicamentos. Foi realizado um levantamento sistemático, através dos bancos de dados PubMed/Medline, Lilacs e SciELO, cuja temática envolveu pesquisas em farmacoeconomia, farmacovigilancia, ecofarmacovigilancia e estudo da utilizagao de medicamentos no Brasil de 2001 a 2019. As publicagóes distribuíram-se de forma desigual entre as regióes brasileiras. Pacientes hipertensos, oncológicos e as gestantes foram os grupos de risco mais citados e os antimicrobianos, psicotrópicos e antineoplásicos os grupos farmacológicos mais discutidos. Custo de cuidados em saúde foi a temática mais abordada no contexto da farmacoeconomia e grande parte dos trabalhos destinou-se a análise e obtengao de dados referentes ao uso de medicamentos e suas reagóes adversas. Em relagao a ecofarmacovigilancia nao foram encontradas publicagóes no Brasil que contemplem essa área. Apesar dos avangos da legislagao farmacoepidemiológica e melhorias nos processos de fiscalizagao, no que tange a vigilancia da produgao, registro, comercializagao e uso de medicamentos, ainda permanecem carencias, quanto ao aporte de uma visao científica direcionada, sobretudo ao gerenciamento e diferentes usos dos recursos terapéuticos, e económicos do sistema de saúde brasileiro, bem como uma visao ambiental referente ao uso de medicamentos.

Abstract Studies in pharmacological and ecopharmacological surveillance make it possible to monitor, identify and minimize harmful effects arising from the use of drugs. Therefore, the present study aimed to describe the current scenario of pharmacoepidemiology and ecopharmacovigilance in Brazil, about the production, registration, marketing, and use of medicines. A systematic survey was carried out through the PubMed/Medline, Lilacs, and SciELO databases, whose theme involved research in pharmacoeconomics, pharmacovigilance, ecopharmacovigilance, and the study of drug use in Brazil from 2001 to 2019. Publications were unevenly distributed between Brazilian regions. Hypertensive patients, cancer patients, and pregnant women were the most cited risk groups, and antimicrobials, psychotropics, and antineoplastics were the most discussed pharmacological groups. Cost of health care was the most discussed topic in the context of pharmacoeconomics and most of the work was aimed at analyzing and obtaining data regarding the use of drugs and their adverse reactions. Regarding ecopharmacovigilance, no publications were found in Brazil covering this area. Despite advances in pharmacoepidemiological legislation and improvements in inspection processes, regarding the surveillance of the production, registration, commercialization, and use of medicines, there are still gaps regarding the contribution of a directed scientific vision, especially to the management and different uses of resources. therapeutic and economic aspects of the Brazilian health system, as well as an environmental vision regarding the use of medicines.

Resumen Los estudios de vigilancia farmacológica y ecofarmacológica permiten controlar, identificar y minimizar los efectos nocivos derivados del uso de los medicamentos. Ante esto, el presente estudio tuvo como objetivo describir el escenario actual de la farmacoepidemiología y la ecofarmacovigilancia en Brasil, en relación con la producción, el registro, la comercialización y el uso de los medicamentos. Se realizó una encuesta sistemática, a través de las bases de datos PubMed/Medline, Lilacs y SciELO, cuya temática involucró investigaciones sobre farmacoepidemiología, farmacovigilancia, ecofarmacovigilancia y estudio del uso de medicamentos en Brasil desde 2001 hasta 2019. Las publicaciones se distribuyeron de forma desigual entre las regiones brasileñas. Los pacientes hipertensos, los pacientes oncológicos y las mujeres embarazadas fueron los grupos de riesgo más citados y los antimicrobianos, los psicotrópicos y los antineoplásicos fueron los grupos farmacológicos más discutidos. El coste de la asistencia sanitaria fue el tema más abordado en el contexto de la farmacoeconomía y la mayoría de los trabajos estaban dirigidos a analizar y obtener datos sobre el uso de los medicamentos y sus reacciones adversas. En cuanto a la ecofarmacovigilancia, no se encontraron publicaciones en Brasil que aborden esta área. A pesar de los avances en la legislación farmacoepidemiológica y de las mejoras en los procesos de inspección, en lo que respecta a la vigilancia de la producción, registro, comercialización y uso de los medicamentos, todavía falta una visión científica dirigida, sobre todo, a la gestión y a los diferentes usos de los recursos terapéuticos y económicos del sistema de salud brasileño, así como una visión ambiental en cuanto al uso de los medicamentos.

Free acquisition of psychotropic drugs by the Brazilian adult population and presence on the National List of Essential Medicines

Abstract The aims of the present study were to estimate the free-of-charge acquisition of psychotropic drugs among Brazilian adults; analyze the distribution of psychotropics according to their presence on the Relação Nacional de Medicamentos Essenciais (RENAME [National List of Essential Medicines]) and acquisition according to the source of funding (free of charge or direct payment); and estimate the proportion of free-of-charge psychotropic drugs according to therapeutic class and presence on the RENAME. This study involved the analysis of data from the 2014 National Survey on the Accessibility, Use and Promotion of the Rational Use of Medicines considering psychotropic drugs used by the adult population (≥20 years; n = 32,348). The prevalence of the acquisition of free-of-charge psychotropic drugs was 53.3% and 64.6% of these drugs were on the RENAME. Among the psychotropic drugs acquired by direct payment, 70.8% were not on the national list. Regarding free-of-charge acquisition according to the therapeutic class and presence on the RENAME, differences were found for antidepressants, anxiolytics and antipsychotics (p <0.05). In conclusion, the most used psychotropic medicines were listed in the RENAME, but free-of-charge acquisition was not provided for all of them

Prevalência e fatores associados à polifarmácia e potenciais interações medicamentosas em adultos na cidade de Manaus: estudo transversal de base populacional, 2019 / Prevalencia y factores asociados a la polifarmacia y posibles interacciones farmacológicas en adultos en la ciudad de Manaus, Amazonas, Brasil: estudio transversal poblacional, 2019 / Prevalence and factors associated with polypharmacy and potential drug interactions in adults in Manaus, Amazonas state, Brazil: a cross-sectional population-based study, 2019

Objetivo: Analisar a prevalência e fatores associados à polifarmácia e a presença de potenciais interações medicamentosas em Manaus, estado do Amazonas, Brasil, em 2019. Métodos: Estudo transversal de base populacional, com adultos de ≥ 18 anos. Entre pessoas em polifarmácia (≥ 5 medicamentos), pesquisou-se a presença de interações medicamentosas na base Micromedex. Razões de prevalências (RP) com intervalos de confiança de 95% (IC95%) foram calculadas por regressão de Poisson com variância robusta, seguindo análise hierárquica e considerando o delineamento amostral complexo. Resultados: Dos 2.321 participantes, 2,8% (IC95% 2,1;3,6) estavam em polifarmácia e, destes, 74,0% apresentaram interações, sendo mais frequentes quatro ou mais interações por pessoa (40,4%) e gravidade alta (59,5%). Polifarmácia foi maior entre idosos (RP = 3,24; IC95% 1,25;8,42), pessoas com saúde ruim (RP = 2,54; IC95% 1,14;5,67), hospitalização prévia (RP = 1,90; IC95% 1,09;3,32) e multimorbidade (RP = 3,20; IC95% 1,53;6,67). Conclusão: A polifarmácia foi mais frequente entre idosos e pessoas com problemas de saúde, que tiveram mais interações medicamentosas.

Objetivo: Analizar la prevalencia y factores asociados a la polifarmacia y la presencia de posibles interacciones farmacológicas en Manaus, estado de Amazonas, Brasil, en 2019. Métodos: Estudio poblacional transversal realizado con adultos con edad ≥ 18 años. Entre personas en polifarmacia (≥ 5 medicamentos), se investigó la presencia de interacciones farmacológicas en Micromedex. Las razones de prevalencia (RP) con intervalos de confianza de 95% (IC95%) se calcularon mediante la regresión de Poisson con varianza robusta, siguiendo análisis jerárquico y considerando el diseño de muestra complejo. Resultados: De los 2.321 participantes, 2,8% (IC95% 2,1;3,6) se encontraban en polifarmacia, de los cuales 74,0% presentaban interacciones, siendo más frecuentes cuatro o más interacciones por persona (40,4%) y de alta gravedad (59,5%). La polifarmacia fue mayor entre los ancianos (RP = 3,24; IC95% 1,25;8,42), personas con mala salud (RP = 2,54; IC95% 1,14;5,67), hospitalización previa (RP = 1,90; IC95% 1,09;3,32) y multimorbilidade (RP = 3,20; IC95% 1,53;6,67). Conclusión: La polifarmacia fue más frecuente entre los ancianos y personas con problemas de salud, que potencialmente tenían más interacciones farmacológicas.

Objective: To assess the prevalence and factors associated with polypharmacy and the presence of potential drug interactions in Manaus, Amazonas state, Brazil, in 2019. Methods: This was a population-based cross-sectional study conducted with adults aged ≥ 18 years. The presence of drug interactions among people on a polypharmacy regimen (≥ 5 drugs) was investigated on the Micromedex database. Prevalence ratios (PR) with 95% confidence intervals (95%CI) were calculated using Poisson regression model with robust variance, following hierarchical analysis and considering the complex sample design. Results: Of the 2,321 participants, 2.8% (95%CI 2.1;3.6) were on polypharmacy regimen, of whom, 74.0% presented drug interactions, usually with four or more drug interactions per person (40.4%) and high severity (59.5%). Polypharmacy was higher among older adults (PR = 3.24; 95%CI 1.25;8.42), people with poor health (PR = 2.54; 95%CI 1.14;5.67), previous hospitalization (PR = 1.90; 95%CI 1.09;3.32) and multimorbidity (PR = 3.20; 95%CI 1.53;6.67). Conclusion: Polypharmacy was more frequent among older adults and people with medical problems, who presented more drug interactions.

Use of medication and associated factors in adults living in Rio Branco, Acre. Use of medication in adults

Abstract We analyzed use of medication and associated factors in adults aged 18-59 years living in Rio Branco, Acre. This is a cross-sectional and population-based study that used a probabilistic sample of the population from rural and urban areas of the city of Rio Branco, Acre. The Prevalence Ratio (PR) was calculated with 95% confidence intervals and associations were estimated by Poisson regression. This study found a 29.4% prevalence ratio of use of medication among individuals aged from 18 to 59 years (685 adults: 473 women and 212 men; producing estimates for 211,902 adults: 110,769 women and 101,133 men). After adjusted analysis, their use was associated with: age (50-59 years, PR: 2.36; 95%CI: 2.29-2.43); women (PR: 1.25; 95%CI: 1.23-1.27); up to elementary school (PR: 1.13; 95%CI: 1.11-1.15); and poor or very poor self-rated health (PR: 1.47; 95%CI: 1.43-1.51). The health conditions associated with use of medication were: number of comorbidities, hypertension, diabetes, insomnia, depression, number of health complaints and use of health services. The most frequently used drugs were those belonging to the following ATC categories: alimentary tract and metabolism, cardiovascular system, nervous system, and the musculoskeletal system.

Anticholinergic burden: First comprehensive analysis using claims data shows large variation by age and sex.

PURPOSE: The cumulative effect of medication inhibiting acetylcholine activity-also known as anticholinergic burden (AB)-can lead to functional and cognitive decline, falls, and death. Given that studies on the population prevalence of AB are rare, we aimed to describe it in a large and unselected population sample. METHODS: Using the German Pharmacoepidemiological Research Database (GePaRD) with claims data from ~20% of the German population we analyzed outpatient drug dispensations in 2016. Based on the Anticholinergic Cognitive Burden (ACB) scale, we classified persons into four categories and determined the cumulative AB as continuous variable. RESULTS: Among 16,470,946 persons (54% female), the prevalence of clinically relevant AB (ACB≥3) was 10% (women) and 7% (men). Below age 40 it was highest in persons ≤18 years (6% both sexes). At older ages (50-59 vs. 90-99 years), prevalence of ACB≥3 increased from 7% to 26% (men) and from 10% to 32% (women). Medication classes contributing to the cumulative AB differed by age: antihistamines, antibiotics, glucocorticoids (≤19 years), antidepressants (20-49 years), antidepressants, cardiovascular medication, antidiabetics (50-64 years), and additionally medication for urinary incontinence/overactive bladder (≥65 years). Medication dispensed by general physicians contributed most to the cumulative AB. CONCLUSION: Although a clinically relevant AB is particularly common in older persons, prevalence in younger age groups was up to 7%. Given the risks associated with AB in older persons, targeted interventions at the prescriber level are needed. Furthermore, risks associated with AB in younger persons should be explored.

Trends in Discharge Prescription of Digoxin After Norwood Operation: An Analysis of Data from the Pediatric Health Information System (PHIS) Database.

Quality improvement efforts have focused on reducing interstage mortality for infants with hypoplastic left heart syndrome (HLHS). In 1/2016, two publications reported that use of digoxin was associated with reduced interstage mortality. The degree to which these findings have affected real world practice has not been evaluated. The discharge medications of neonates with HLHS undergoing Norwood operation between 1/2007 and 12/2018 at Pediatric Health Information Systems Database hospitals were studied. Mixed effects models were calculated to evaluate the hypothesis that the likelihood of digoxin prescription increased after 1/2016, adjusting for measurable confounders with furosemide and aspirin prescription measured as falsification tests. Interhospital practice variation was measured using the median odds ratio. Over the study period, 6091 subjects from 45 hospitals were included. After adjusting for measurable covariates, discharge after 1/2016 was associated with increased odds of receiving digoxin (OR 3.9, p < 0.001). No association was seen between date of discharge and furosemide (p = 0.26) or aspirin (p = 0.12). Prior to 1/2016, the likelihood of receiving digoxin was decreasing (OR 0.9 per year, p < 0.001), while after 1/2016 the rate has increased (OR 1.4 per year, p < 0.001). However, there remains significant interhospital variation in the likelihood of receiving digoxin even after adjusting for known confounders (median odds ratio = 3.5, p < 0.0001). Following publication of studies describing an association between digoxin and improved interstage survival, the likelihood of receiving digoxin at discharge increased without similar changes for furosemide or aspirin. Despite concerted efforts to standardize interstage care, interhospital variation in pharmacotherapy in this vulnerable population persists.

A systematic assessment of the association between frequently prescribed medicines and the risk of common cancers: a series of nested case-control studies.

BACKGROUND: Studies systematically screening medications have successfully identified prescription medicines associated with cancer risk. However, adjustment for confounding factors in these studies has been limited. We therefore investigated the association between frequently prescribed medicines and the risk of common cancers adjusting for a range of confounders. METHODS: A series of nested case-control studies were undertaken using the Primary Care Clinical Informatics Unit Research (PCCIUR) database containing general practice (GP) records from Scotland. Cancer cases at 22 cancer sites, diagnosed between 1999 and 2011, were identified from GP records and matched with up to five controls (based on age, gender, GP practice and date of registration). Odds ratios (OR) and 95% confidence intervals (CI) comparing any versus no prescriptions for each of the most commonly prescribed medicines, identified from prescription records, were calculated using conditional logistic regression, adjusting for comorbidities. Additional analyses adjusted for smoking use. An association was considered a signal based upon the magnitude of its adjusted OR, p-value and evidence of an exposure-response relationship. Supplementary analyses were undertaken comparing 6 or more prescriptions versus less than 6 for each medicine. RESULTS: Overall, 62,109 cases and 276,580 controls were included in the analyses and a total of 5622 medication-cancer associations were studied across the 22 cancer sites. After adjusting for comorbidities 2060 medicine-cancer associations for any prescription had adjusted ORs greater than 1.25 (or less than 0.8), 214 had a corresponding p-value less than or equal to 0.01 and 118 had evidence of an exposure-dose relationship hence meeting the criteria for a signal. Seventy-seven signals were identified after additionally adjusting for smoking. Based upon an exposure of 6 or more prescriptions, there were 118 signals after adjusting for comorbidities and 82 after additionally adjusting for smoking. CONCLUSIONS: In this study a number of novel associations between medicine and cancer were identified which require further clinical and epidemiological investigation. The majority of medicines were not associated with an altered cancer risk and many identified signals reflected known associations between medicine and cancer.

Prevalence and factors associated with the consumption of folic acid and iron in pregnant women in the BRISA cohort / Prevalência e fatores associados ao uso de ácido fólico e ferro em gestantes da coorte BRISA

Abstract Objectives: to describe the prevalence and factors associated with the consumption of folic acid and iron among puerperal women in the city of São Luís, Maranhão. Methods: a cross-sectional study with 4,036 puerperal women through a standardized questionnaire. The dependent variables (outcomes) were: the consumption of folic acid during pregnancy, iron and folic acid before pregnancy. The independent variables: age; schooling; skin color; marital status; income; planned pregnancy; place and number of prenatal consultations. Statistical analyzes were performed on STATA 14.0. For the first two outcomes, Poisson model with a robust variance was used. And for the last one, logistic regression. Results: the prevalence of consuming folic acid and iron during pregnancy were, respec-tively, 77.27% and 84.98%. However, only 0.37% reported the consume of folic acid and iron before pregnancy. In the adjusted analysis, the variables associated with the consumption of folic acid during pregnancy were: schooling and income; the consume of iron during preg-nancy, age only; and for those who consumed folic acid before pregnancy, no variable was statistically significant. Conclusions: high percentage of puerperal women who consumed folic acid and iron supplements during pregnancy, however, the recommended consumption of folic acid before pregnancy was low and maternal, social and economic factors influence the consumption of these supplements.

Resumo Objetivos: descrever prevalência e fatores associados ao uso deácido fólico e ferro entre puérperas do município de São Luís, Maranhão. Métodos: estudo transversal com 4.036 puérperas através de questionário padronizado. As variáveis dependentes (desfechos) foram: uso durante a gestação de ácido fólico, ferro e ácido fólico antes da gestação. As variáveis independentes: idade; escolaridade; cor da pele; situação conjugal; renda; gravidez planejada; local e número de consultas do pré-natal. As análises estatísticas foram realizadas no STATA 14.0. Para os dois primeiros desfechos, utilizou-se modelo de Poisson com variância robusta. Para o último, regressão logística. Resultados: a prevalência do uso de ácido fólico e ferro durante a gestação foram, respectivamente, 77,27% e 84,98%. Entretanto, apenas 0,37% declararam uso antes da gestação. Na análise ajustada, as variáveis associadas com uso de ácido fólico durante a gestação foram: escolaridadee renda; parausode ferro durante a gestação, apenas a idade; e para as que fizeram uso de ácido fólico antes da gestação, nenhuma variável mostrou-se estatisticamente significativa. Conclusões: alto percentual de puérperas fez uso de suplementos de ácido fólico e ferro-durante a gestação, porém o uso recomendado de ácido fólico antes da gestação mostrou-se baixo e que fatores maternos, sociais e econômicos influenciam no consumo destes suple-mentos.

Pharmacoepidemiology of testosterone: Impact of reimbursement policy on curbing off-label prescribing.

OBJECTIVES: To estimate the impact on testosterone prescribing over 3 years following the 2015 tightening of Pharmaceutical Benefits Scheme (PBS) criteria. DESIGN: Analysis of testosterone prescribing data from PBS and private (non-PBS) sources between 2012 and 2018 covering 2015 change in PBS prescribing criteria. MAIN OUTCOME MEASURES: New and total PBS testosterone prescriptions estimating usage by quarter analyzed by product type, patient age-group, indication and prescriber type. Total national testosterone prescriptions (private plus PBS) was verified from an independent data supplier (IQVIA). RESULTS: PBS usage peaked in 2014 declining by 30% in 2017-8 with PBS prescribing covering a fall from 97.6% by usage in 2014 to 74% in 2017-18 of all testosterone prescribing. The tighter 2015 PBS restrictions sustained the selective reduction in GP initiation of prescriptions for middle-aged men without pathological hypogonadism whereas specialist initiations and prescription for adult hypogonadism or pediatric/prepubertal indications were largely unaffected. CONCLUSIONS: The tightening of PBS criteria from 1 April 2015 to curb off-label prescribing remained effective and selective over 3 years yet total national testosterone prescribing continued with little change, reflecting a shift to private prescriptions. The continuation of off-label testosterone prescribing for unproven indications suggests that long-term androgen dependence is created in men without pathological hypogonadism who commence testosterone. This highlights the need to avoid prescribing testosterone to men without pathological hypogonadism in the absence of sound evidence of efficacy and safety, the latter including the little unrecognized risks of long-term androgen dependency when trying to quit.

Tuberculosis drug safety and pharmacovigilance in health system of Kosova: A cross-sectional analysis.

BACKGROUND: Tuberculosis (TB) remains a significant worldwide social and life-threatening epidemiological problem. Because this disease requires multiple drug treatment and prolonged therapy for several months, followed by a high probability of adverse effects (AEs), we assessed AE monitoring for anti-TB drugs in the Health Care System of Kosova. METHODS: This survey was a cross-sectional analysis performed at the primary, secondary and tertiary health care levels in Kosova. We included 930 registered tuberculosis patients within three levels of this health system in our study. Furthermore, we interviewed 62 physicians and 71 nurses at TB health facilities. Data were collected from official TB registers and personal contact with patients for 12 months. RESULTS: The representative age group was 19 to 29 years (30.49%), followed by a group of patients aged >60 years (23.23%). Among 930 patients treated with TB drugs, the total incidence of adverse AEs was 29.03%. Female TB patients had a higher rate of AEs than did male patients (33.56% vs 28.84%, respectively). The highest incidence of registered AEs was recorded in the gastrointestinal system (270, 80.83%), followed by the central nervous system (CNS, 7.50%) and was lower in other organ systems. The reporting of anti-TB drug effects by medical staff (TB medical doctor and TB medical nurse) at different levels of TB medical settings occurred among 62.90% of medical doctors and 81.69% of nurses. Only 53.23% of medical doctors and 46.48% of nurses completed pharmacovigilance training. CONCLUSION: The pharmacovigilance approach in Health System of Kosova is not comprehensible and not systematic. The relatively low incidence of AEs among TB patients is due under reporting of these by medical staff. The knowledge, attitudes, and adherence of medical staff reveal low awareness for pharmacovigilance activities, and this concern should be addressed to reinforce this important issue for the safe treatment of TB patients.

Spillover effects of state medicaid antipsychotic prior authorization policies in US commercially insured youth.

PURPOSE: To evaluate spillover effects of Medicaid antipsychotic prior authorization (PA) policies among commercially insured youth. METHODS: Commercially insured youth residing in nine US states that implemented PA exclusively for antipsychotics in 2011 or 2012 were identified using a 10% random sample of enrollees in the IQVIA PharMetrics Plus database spanning 2007 to 2015. Youth were included if they were ≤18 years, met the age criteria of the PA at the time of dispensing, and had at least 1 month of prescription drug coverage from 2007 to 2015. The primary outcome of interest was the monthly prevalence of antipsychotics. We implemented segmented regression of interrupted time series analysis to estimate changes in the monthly prevalence of targeted medications, overall and stratified by age. Trends were compared in the 4-year period before and the 3-year period after implementation of PA policies. RESULTS: Antipsychotics prescribing significantly decreased 6.74/10 000 (95% CI, -9.04 to -4.44) enrollees per month immediately after PA implementation. However, PA was not associated with significant long-term trend changes (-0.06; 95% CI, -0.16 to 0.03). Antipsychotic prescribing in children <12 years-old significantly decreased 0.14/10 000 (95% CI, -0.21 to -0.07) enrollees per month after PA implementation, while prescribing in adolescents 12 to 18 years-old significantly increased 0.32/10 000 (95% CI, 0.16 to 0.47) enrollees per month. CONCLUSION: While Medicaid PA polices for antipsychotic oversight did not affect overall prescribing, there were spillover effects in U.S. commercially insured children <12 years-old. This suggests that state-level Medicaid policies intended to improve the quality of care and safe use of antipsychotics can have broad reach.

Quality of reporting of drug exposure in pharmacoepidemiological studies.

PURPOSE: Exposure definitions vary across pharmacoepidemiological studies. Therefore, transparent reporting of exposure definitions is important for interpretation of published study results. We aimed to assess the quality of reporting of exposure to identify where improvement may be needed. METHOD: We systematically reviewed observational pharmacoepidemiological studies that used routinely collected health data, published in 2017 in six pharmacoepidemiological journals. Reporting of exposure was scored using 11 items of the ISPE-ISPOR guideline on reporting of pharmacoepidemiological studies. RESULTS: Of the 91 studies included, all studies reported the type of exposure (100%), while most reported the exposure risk window (85%) and the exposure assessment window (98%). Operationalization of the exposure window was described infrequently: 16% (14/90) of the studies explicitly reported the presence or absence of an induction period if applicable, 11% (5/47), and 35% (17/49) reported how stockpiling and gaps between exposure episodes were handled, respectively, and 35% (17/49) explicitly mentioned the exposure extension. Switching/add-on was reported in 62% (50/81). How switching between drugs was dealt with and specific drug codes were reported in 52 (57%) and 24 (26%) studies, respectively. CONCLUSION: Publications of pharmacoepidemiological studies frequently reported the type of exposure, the exposure risk window, and the exposure assessment window. However, more details on exposure assessment are needed, especially when it concerns the operationalization of the exposure risk window (eg, the presence or absence of an induction period or exposure extension, handling of stockpiling and gaps, and specific codes), to allow for correct interpretation, reproducibility, and assessment of validity.

Real-world data in Saudi Arabia: Current situation and challenges for regulatory decision-making.

PURPOSE: To present the process of establishing a pharmacoepidemiological database in Saudi Arabia, challenges and models used. METHODS: The database establishment has started in 2017 by piloting the conversion of electronic health records of one hospital to the Observational Health Data Sciences and Informatics (OHDSI), Observational Medical Outcomes Partnership's Common Data Model (OMOP). RESULTS: During the pilot phase we have faced several challenges such as limited contribution in providing data by local medical institution due to uncertainty about data governance, diversity of systems used by hospitals, inconsistent coding of medical information, and limited awareness about data structure from participating hospital. The pilot phase was completed in 2019 containing information about patient attributes, medical care, therapies, and other additional services for around 130 000 patients in Saudi Arabia. The majority of patients were below the age of 50 years (89%), and acute respiratory infections were the most frequent diagnosis. The data quality was acceptable and no major anomalies were detected during the conversion. CONCLUSIONS: We demonstrated a successful creation of a pilot database using OHDSI Common Data Model. Our experience with the pilot database could be extended to other institutions to create a national dataset that could be used to generate real-world evidence.

Empirical assessment of case-based methods for drug safety alert identification in the French National Healthcare System database (SNDS): Methodology of the ALCAPONE project.

OBJECTIVES: To introduce the methodology of the ALCAPONE project. BACKGROUND: The French National Healthcare System Database (SNDS), covering 99% of the French population, provides a potentially valuable opportunity for drug safety alert generation. ALCAPONE aimed to assess empirically in the SNDS case-based designs for alert generation related to four health outcomes of interest. METHODS: ALCAPONE used a reference set adapted from observational medical outcomes partnership (OMOP) and Exploring and Understanding Adverse Drug Reactions (EU-ADR) project, with four outcomes-acute liver injury (ALI), myocardial infarction (MI), acute kidney injury (AKI), and upper gastrointestinal bleeding (UGIB)-and positive and negative drug controls. ALCAPONE consisted of four main phases: (1) data preparation to fit the OMOP Common Data Model and select the drug controls; (2) detection of the selected controls via three case-based designs: case-population, case-control, and self-controlled case series, including design variants (varying risk window, adjustment strategy, etc.); (3) comparison of design variant performance (area under the ROC curve, mean square error, etc.); and (4) selection of the optimal design variants and their calibration for each outcome. RESULTS: Over 2009-2014, 5225 cases of ALI, 354 109 MI, 12 633 AKI, and 156 057 UGIB were identified using specific definitions. The number of detectable drugs ranged from 61 for MI to 25 for ALI. Design variants generated more than 50 000 points estimates. Results by outcome will be published in forthcoming papers. CONCLUSIONS: ALCAPONE has shown the interest of the empirical assessment of pharmacoepidemiological approaches for drug safety alert generation and may encourage other researchers to do the same in other databases.

Quantifying how small variations in design elements affect risk in an incident cohort study in claims.

BACKGROUND: Epidemiological study reporting is improving but is not transparent enough for easy evaluation or replication. One barrier is insufficient details about design elements in published studies. METHODS: Using a previously conducted drug safety evaluation in claims as a test case, we investigated the impact of small changes in five key design elements on risk estimation. These elements are index day of incident exposure's determination of look-back or follow-up periods, exposure duration algorithms, heparin exposure exclusion, propensity score model variables, and Cox proportional hazard model stratification. We covaried these elements using a fractional factorial design, resulting in 24 risk estimates for one outcome. We repeated eight of these combinations for two additional outcomes. We measured design effects on cohort sizes, follow-up time, and risk estimates. RESULTS: Small changes in specifications of index day and exposure algorithm affected the risk estimation process the most. They affected cohort size on average by 8 to 10%, follow-up time by up to 31%, and magnitude of log hazard ratios by up to 0.22. Other elements affected cohort before matching or risk estimate's precision but not its magnitude. Any change in design substantially altered the matched control-group subjects in 1:1 matching. CONCLUSIONS: Exposure-related design elements require attention from investigators initiating, evaluating, or wishing to replicate a study or from analysts standardizing definitions. The methods we developed, using factorial design and mapping design effect on causal estimation process, are applicable to planning of sensitivity analyses in similar studies.

Using nationally representative survey data for external adjustment of unmeasured confounders: An example using the NHANES data.

PURPOSE: To evaluate the use of data from population-based surveys such as the National Health and Nutrition Examination Survey (NHANES) for external adjustment for confounders imperfectly measured in health care databases in the United States. METHODS: Our example study used Medicaid Analytic eXtract (MAX) data to estimate the relative risk (RR) for prenatal serotonin-norepinephrine reuptake inhibitors (SNRIs) exposure and cardiac defects. Smoking and obesity are known confounders poorly captured in databases. NHANES collects information on lifestyle factors, depression, and prescription medications. External adjustment requires information on the prevalence of confounders and their association with SNRI use; which was obtained from the NHANES. It also requires estimates of their association with the outcome, which were based on the literature and allowed us to correct the RR using sensitivity analyses. RESULTS: In MAX, the RR for the association between prenatal SNRI exposure and cardiac defects was 1.51 unadjusted and 1.20 adjusted for measured confounders and restricted to women with depression. In NHANES, among women of childbearing age with depression, the prevalence of smoking was 60.2% (95% Confidence Interval 43.2, 74.3) for SNRI users and 44.1% (39.6, 48.8) for nonusers of antidepressants. The corresponding estimates for obesity were 59.2% (43.2, 74.3) and 40.5% (35.9, 45.0), respectively. If the associations between smoking and obesity with cardiac defects are independent from each other and from other measured confounders, additional adjustment for smoking and obesity would move the RR from 1.20 to around 1.10. CONCLUSION: National surveys like NHANES are readily available sources of information on potential confounders and they can be used to assess and improve the validity of RR estimates from observational studies missing data on known risk factors.

The epidemiology of antidepressant use in South Korea: Does short-term antidepressant use affect the relapse and recurrence of depressive episodes?

BACKGROUND: The duration of antidepressant use affects the treatment of depression. Using the National Health Insurance database, which covers almost the entire national population, we verified the factors associated with the inadequate short-term use of initially prescribed antidepressants and their effects on the relapse and recurrence of depressive episodes. METHODS: There were 752,190 patients included who had been newly prescribed antidepressants in 2012 with the diagnosis of depressive disorder. They were followed-up until December 31, 2015. They were classified as short-term and long-term antidepressant users depending on whether they used a specific initial antidepressant for at least four weeks. Sociodemographic, clinical, and medical utilization factors affecting the duration of antidepressant use were investigated. We also identified whether the duration of antidepressant use affected the risk of relapse and recurrence, which was defined by the restarting of antidepressants. RESULTS: Initial antidepressants were taken for less than 28 days by 458,057 (60.84%) patients. Tricyclic antidepressants were used as the initial antidepressant more frequently than selective serotonin reuptake inhibitors (64.5% versus 19.3%). The type of initial antidepressant, polypharmacy, psychiatric and medical comorbidities, type of insurance coverage, and type of medical institution visited were associated with short-term use. Short-term use marginally increased the risk of relapse and recurrence of depressive episodes (Hazard ratio: 1.06, 95% confidence intervals 1.048-1.075). CONCLUSIONS: Short-term antidepressant use is widespread in Korea, and assessment in various aspects are necessary to set proper treatment plans.

A comparison of opioid-involved fatalities captured in the National Poison Data System to data derived from US death certificate literal text.

PURPOSE: The purpose of the study is to describe and compare the number and characteristics of opioid-involved fatal cases captured in the National Poison Data System (NPDS) and in US death certificates. METHODS: NPDS, which collects data on all calls to US poison control centers, and Drug-Involved Mortality (DIM), which combines information from literal text of US death certificates and National Vital Statistics Systems, were queried for opioid-involved fatal cases from 2010 to 2015. Characteristics of the two case series were compared. RESULTS: DIM contained 154 016 opioid-involved overdose deaths, and NPDS contained 2524 fatal opioid exposures, a ratio of 61:1. The number of opioid deaths remained stable in NPDS but increased in DIM over the 6-year period. On average, deaths involving opioids with higher mean dosage strength (in morphine milligram equivalents) per unit among dispensed prescriptions were more likely to be captured in DIM relative to NPDS, as compared with those with a lower mean dosage strength per unit. The increase in fentanyl-related deaths seen in DIM since 2013 was not observed in NPDS. CONCLUSIONS: NPDS is a valuable drug safety surveillance resource due to its timeliness and drug specificity. However, it captures only a small fraction of opioid-involved fatal poisonings, and comparisons with data derived from death certificate literal text indicate that caution is warranted in making inferences about opioid-involved fatality trends over time or comparisons across opioids.

Agreement between self-reported and registry-based use of sleep medications and tranquilizers.

PURPOSE: The purpose of the present study was to assess the agreement between self-reported use of sleep medications and tranquilizers and dispensed hypnotics and anxiolytics. METHODS: Self-reported medication use was obtained from the population-based survey Health and Environment in Oslo (HELMILO) (2009-2010) (n = 13 019). Data on dispensed hypnotics and anxiolytics were obtained from the Norwegian Prescription Database (NorPD). As measures of validity, we calculated sensitivity and specificity using both self-reports and prescription records as the reference standard. Furthermore, we calculated Cohen's kappa. Current self-reported medication use was compared with prescription data in time windows of both 100 and 200 days preceding questionnaire completion. RESULTS: The highest sensitivity was observed for current sleep medication use in the 100-day time window (sensitivity = 0.76, 95% confidence interval [CI]: 0.74, 0.79) when using prescription records as the reference standard. Sensitivity was generally lower for tranquilizers compared with sleep medications. Cohen's kappa showed the highest agreement for the 200-day time window with substantial agreement for sleep medications (kappa = 0.64; 95% CI: 0.62, 0.67) and moderate agreement for tranquilizers (kappa = 0.45; 95% CI: 0.41, 0.48). CONCLUSIONS: The present study suggests moderate to substantial agreement between self-reported use of sleep medications and tranquilizers and dispensed drugs in a general adult population. The magnitude of agreement varied according to drug category and time window. Since self-reported and registry-based use of these drug classes does not match each other accurately, limitations of each data source should be considered when such medications are applied as the exposure or outcome in epidemiologic studies.