Methodological Quality of Pulmonary Arterial Hypertension Treatment Evidence-Based Guidelines: A Systematic Review Using the AGREE II and AGREE REX Tools.

PURPOSE: Pulmonary arterial hypertension (PAH) is a progressive disease with a poor prognosis, and its management should be grounded in well-developed clinical practice guidelines (CPG). Thus, we critically assess the methodological quality of the available CPG for pharmacological treatments for PAH. METHODS: A systematic review (CRD42023387168) was performed in PubMed, Cochrane, Embase, and Tripdatabase (Jan-2023). Eligible records were appraised by four reviewers using the Appraisal of Guidelines, Research, and Evaluation Collaboration tool (AGREE II) and the complementary tool for assessing recommendations' quality and certainty, AGREE REX. Descriptive statistics were used to summarize the data. RESULTS: Overall, 31 guidelines, mainly authored by professional societies (90%), targeting only physicians as primary users (84%), were identified. Guidelines presented a moderate overall quality (scores of 63% and 51% in AGREE II and AGREE REX, respectively), with a few domains showing slight improvements over the years. AGREE II "Scope and Purpose" (94%) and "Presentation Clarity" (99%) domains obtained the highest scores. The items related to "Stakeholder involvement," "Editorial independence," and "Clinical applicability" (AGREE REX) were fairly reported. Conversely, CPG lacks rigor in development (32% score, AGREE II), scarcely discusses the role of stakeholders, and provides deficient data on the implementation of recommendations (scores of 35% and 46% in AGREE II and AGREE REX, respectively). No differences in the quality of guidelines published by different developers or countries were observed (p > 0.05). CONCLUSION: Methodological weaknesses are common among guidelines addressing PAH treatment, especially regarding scientific rigor, stakeholders' values and preferences, and facilitators and barriers to implementability. Particular attention should be given to developing future guidelines.

Cost of adverse drug events related to potentially inappropriate medication use: A systematic review.

BACKGROUND: The use of potentially inappropriate medications (PIMs) for older people is associated with worse health outcomes owing to the occurrence of adverse drug events (ADEs) and drug interactions, leading to increased health care costs. OBJECTIVES: Identify the costs of ADEs related to PIMs use, in addition to the costs predictors. METHODS: A systematic review was conducted in the PubMed and Scopus databases (until February, 2022), and the report of this study was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Interventional and observational studies that reported costs of ADEs regardless of perspective (i.e., payer) were considered. Reporting and methodological quality were assessed using the tool proposed by Larg and Moss for evaluating cost-of-illness studies. RESULTS: A total of 20 (21 publications), published between 2001 and 2020, were included (236,888,744 older people). The ADEs costs related to PIMs use were mostly related to the use of health services (hospitalization [n = 7], health care expenses [n = 7], and emergency department visits [n = 3]). Among the 8 studies that reported P value, 7 identified higher costs for PIM users than non-PIM users. Three studies reported cost predictors, being highest number of PIMs in use, age older than 75 years, male gender, general health status in older people in use of benzodiazepines, and drug interactions in older people diagnosed as having dementia. Regarding to assessment of reporting and methodological quality, all studies had at least one limitation (answer "no"). CONCLUSIONS: Our findings suggest that PIMs use is associated with higher costs of hospitalization, health care expenses, and visits to emergency department owing to ADEs, regardless of PIMs in use, health service, perspective, and screening tools used for PIMs identification. However, these findings should be interpreted with caution because all studies had at least one methodological limitation.

Genetic polymorphisms associated with upper gastrointestinal bleeding: a systematic review.

Non-variceal upper gastrointestinal bleeding (non-variceal UGIB) is a frequent and severe adverse drug reaction. Idiosyncratic responses due to genetic susceptibility to non-variceal UGIB has been suggested. A systematic review was conducted to assess the association between genetic polymorphisms and non-variceal UGIB. Twenty-one publications and 7134 participants were included. Thirteen studies evaluated genetic polymorphism in patients exposed to non-steroidal anti-inflammatory drugs, low-dose aspirin, and warfarin. Eight studies present at least one methodological problem. Only six studies clearly defined that the outcome evaluated was non-variceal UGIB. Genetic polymorphisms involved in platelet activation and aggregation, angiogenesis, inflammatory process, and drug metabolism were associated with risk of non-variceal UGIB (NOS3, COX-1; COX-2; PLA2G7; GP1BA; GRS; IL1RN; F13A1; CDKN2B-AS1; DPP6; TBXA2R; TNF-alpha; VKORC1; CYP2C9; and AGT). Further well-designed studies are needed (e.g., clear restriction to non-variceal UGIB; proper selection of participants; and adjustment of confounding factors) to provide strong evidence for pharmacogenetic and personalized medicine.

Application of trigger tools for detecting adverse drug events in older people: A systematic review and meta-analysis.

OBJECTIVE: To identify trigger tools applied to detect adverse drug events (ADEs) in older people and describe their utility and performance. METHODS: A systematic review was conducted in the PubMed, Lilacs, and Scopus databases (January 2024). Studies that developed, applied, or validated trigger tools and evaluated their utility and/or performance for detecting ADEs in older people were considered. Direct proportion meta-analyses using the inverse-variance method were performed for prevalence of ADEs and positive predictive value (PPV). RESULTS: Twenty-four studies (25 publications) were included. Twelve trigger tools were identified, of which six were developed for detecting ADEs in older population, four developed for general population and modified for older people, and two developed for general population. No tools for detecting ADEs in older people receiving palliative care or hospitalized in intensive or surgical care units were found. The performance of triggers was presented through PPV (11.5-71%), negative predictive values (83.3%), and sensitivity (30-94.8%). The overall PPV was 33.3% (95%CI: 32.5-34.2%). Triggers with good performance were changes in plasma levels of digoxin, glucose, and potassium; changes in international normalized ratio; abrupt medication stop; hypotension; and constipation. The prevalence of ADEs ranged from 2.8 to 66%, with overall prevalence of ADEs of 20% (95%CI: 19.3-20.8%). Preventability ranged from 8.4 to 94.4%. Metabolic or electrolyte disturbances induced by diuretics, constipation induced by opioids, and falls and delirium induced by benzodiazepines were the most prevalent ADEs. CONCLUSION: The trigger tools are flexible and easy to apply, and they can contribute to the detection of ADEs, their associated risk factors, the level of harm, and preventability in different health settings. However, there is no consensus on good or poor values of PPV, which indicate the performance of triggers. Furthermore, there is limited evidence regarding the evaluation of performance through negative predictive value, sensitivity, and specificity. PROSPERO: CRD42022379893.

Mapping the characteristics, concepts and methodologies of matching-adjusted indirect comparison studies assessing pharmacological therapies in oncology: a scoping review protocol.

INTRODUCTION: Matching-adjusted indirect comparison (MAIC) studies are a subtype of indirect comparison, which uses propensity score weighting to enhance comparability. This method adjusts aggregated data based on covariables from individual patient data from studies to produce population-adjusted indirect comparisons. Some national Health Technology Assessment agencies have recently received submissions containing MAIC models. However, there can be a lack of confidence in its estimates when they are poorly reported and inconsistent with other techniques. The objective of this study is to map the characteristics, concepts and methodology of MAIC studies used for pharmacological therapies in the field of oncology. METHODS AND ANALYSIS: A scoping review methodology will be applied following the Joanna Briggs Institute framework and the results will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews. Studies that used MAIC to compare treatments in oncology conditions will be considered eligible. A systematic search will be conducted in PubMed, Embase and the Cochrane Library. No restriction of location or language will be applied. Study screening will be documented and presented in a Preferred Reporting Items for Systematic reviews and Meta-Analyses flow diagram. Data will be extracted and recorded on a predefined data form and will be presented in a tabular form accompanied by a descriptive summary. ETHICS AND DISSEMINATION: No ethical approval is required for this study. The results of this scoping review will be disseminated through peer-reviewed publications.

Hydroxychloroquine for Non-Hospitalized COVID-19 Patients: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. / Hidroxicloroquina para Pacientes com COVID-19 não Hospitalizados: Uma Revisão Sistemática e Metanálise de Ensaios Clínicos Randomizados.

BACKGROUND: Previous systematic reviews have identified no benefit of hydroxychloroquine and chloroquine in non-hospitalized COVID-19 patients. After publication of these reviews, the results of COPE, the largest randomized trial conducted to date, became available. OBJECTIVES: To conduct a systematic review and meta-analyses of randomized clinical trials (RCTs) to synthesize the evidence on the efficacy and safety of hydroxychloroquine and chloroquine for non-hospitalized COVID-19 patients compared to placebo or standard of care. METHODS: Searches were conducted in PubMed, Embase, The Cochrane Library, and ClinicalTrials.gov complemented by manual search. Pairwise meta-analyses, risk of bias, and evidence certainty assessments were conducted, including optimal information size analysis (OIS). A level of significance of 0.05 was adopted in the meta-analysis. PROSPERO: CRD42021265427. RESULTS: Eight RCTs with 3,219 participants were included. COVID-19 hospitalization and any adverse events rates were not significantly different between hydroxychloroquine (5.6% and 35.1%) and control (7.4% and 20.4%) (risk ratio, RR, 0.77, 95% confidence interval, CI, 0.57-1.04, I2: 0%; RR 1.78, 95%-CI 0.90; 3.52, I2: 93%, respectively). The OIS (7,880) was not reached for COVID-19 hospitalization, independently of the simulation for anticipated event rate and RR reduction estimate. CONCLUSION: Evidence of very low certainty showed lack of benefit with hydroxychloroquine in preventing COVID-19 hospitalizations. Despite being the systematic review with the largest number of participants included, the OIS, considering pre-vaccination response to infection, has not yet been reached.

FUNDAMENTO: Revisões sistemáticas anteriores não identificaram benefício do uso da hidroxicloroquina ou da cloroquina em pacientes com COVID-19 não hospitalizados. Após a publicação dessas revisões, os resultados do COPE, o maior ensaio clínico randomizado até hoje, tornaram-se disponíveis. OBJETIVOS: Conduzir uma revisão sistemática e metanálise de ensaios clínicos randomizados (ECRs) para sintetizar as evidências sobre a eficácia e a segurança da hidroxicloroquina e da cloroquina em pacientes com COVID-19 não hospitalizados em comparação a controle ou tratamento padrão. MÉTODOS: As buscas foram conduzidas nos bancos de dados PubMed, Embase, The Cochrane Library e ClinicalTrials.gov, e complementadas por busca manual. Foram realizadas metanálises diretas e avaliações de risco de viés e certeza da evidência, incluindo análise do tamanho ótimo da informação (OIS, optimal information size). Um nível de significância de 0,05 foi adotado na metanálise. PROSPERO: CRD42021265427. RESULTADOS: Oito ECRs com 3219 participantes foram incluídos. As taxas de internação por COVID-19 e de eventos adversos não foram significativamente diferentes entre hidroxicloroquina (5,6% e 5,1%) e controle (7,4% e 20,4%) [risco relativo (RR) 0,77, intervalo de confiança 95% (IC95%), 0,57-1,04, I2: 0%; RR 1,78, IC95% 0,90; 3,52, I2: 93%, respectivamente)]. O OIS (7880) não foi alcançado para hospitalização por COVID-19, independentemente da simulação para a taxa de evento e redução do RR estimados. CONCLUSÃO: A evidência de muito baixa qualidade indicou falta de benefício com hidroxicloroquina em prevenir internações por COVID-19. Apesar de ser a revisão sistemática com o maior número de participantes incluídos, o OIS, considerando a resposta à infecção anterior à vacinação, não foi atingido.

Economic burden of respiratory syncytial and parainfluenza viruses in children of upper-middle-income countries: a systematic review.

OBJECTIVE: To identify and assess the current evidence available about the costs of managing hospitalized pediatric patients diagnosed with Respiratory Syncytial Virus (RSV) and Parainfluenza Virus Type 3 (PIV3) in upper-middle-income countries. METHODS: The authors conducted a systematic review across seven key databases from database inception to July 2022. Costs extracted were converted into 2022 International Dollars using the Purchasing Power Parity-adjusted. PROSPERO identifier: CRD42020225757. RESULTS: No eligible study for PIV3 was recovered. For RSV, cost analysis and COI studies were performed for populations in Colombia, China, Malaysia, and Mexico. Comparing the total economic impact, the lowest cost per patient at the pediatric ward was observed in Malaysia ($ 347.60), while the highest was in Colombia ($ 709.66). On the other hand, at pediatric ICU, the lowest cost was observed in China ($ 1068.26), while the highest was in Mexico ($ 3815.56). Although there is no consensus on the major cost driver, all included studies described that the medications (treatment) consumed over 30% of the total cost. A high rate of inappropriate prescription drugs was observed. CONCLUSION: The present study highlighted how RSV infection represents a substantial economic burden to health care systems and to society. The findings of the included studies suggest a possible association between baseline risk status and expenditures. Moreover, it was observed that an important amount of the cost is destinated to treatments that have no evidence or support in most clinical practice guidelines.

Cost of Illness in Patients With COVID-19 Admitted in Three Brazilian Public Hospitals.

OBJECTIVES: The severity and transmissibility of COVID-19 justifies the need to identify the factors associated with its cost of illness (CoI). This study aimed to identify CoI, cost predictors, and cost drivers in the management of patients with COVID-19 from hospital and Brazil's Public Health System (SUS) perspectives. METHODS: This is a multicenter study that evaluated the CoI in patients diagnosed of COVID-19 who reached hospital discharge or died before being discharged between March and September 2020. Sociodemographic, clinical, and hospitalization data were collected to characterize and identify predictors of costs per patients and cost drivers per admission. RESULTS: A total of 1084 patients were included in the study. For hospital perspective, being overweight or obese, being between 65 and 74 years old, or being male showed an increased cost of 58.4%, 42.9%, and 42.5%, respectively. From SUS perspective, the same predictors of cost per patient increase were identified. The median cost per admission was estimated at US$359.78 and US$1385.80 for the SUS and hospital perspectives, respectively. In addition, patients who stayed between 1 and 4 days in the intensive care unit (ICU) had 60.9% higher costs than non-ICU patients; these costs significantly increased with the length of stay (LoS). The main cost driver was the ICU-LoS and COVID-19 ICU daily for hospital and SUS perspectives, respectively. CONCLUSIONS: The predictors of increased cost per patient at admission identified were overweight or obesity, advanced age, and male sex, and the main cost driver identified was the ICU-LoS. Time-driven activity-based costing studies, considering outpatient, inpatient, and long COVID-19, are needed to optimize our understanding about cost of COVID-19.

A comprehensive look at explicit screening tools for potentially inappropriate medication: A systematic scoping review.

OBJECTIVE: To map explicit screening tools to identify potentially inappropriate medication (PIMs), and the characteristics and limitations of these tools. Including PIMs-interactions, therapeutic alternatives and the clinical management of PIMs. METHODS: A systematic scoping review was conducted in PubMed and Scopus (until May 2021). The number of PIMs listed as essential drugs was identified in Model List of Essential Medicines by the World Health Organization (WHO) and National List of Essential Medicines (Brazil). In addition to reporting the therapeutic alternatives and clinical management proposed by explicit screening tools to identify PIMs, we suggested our own alternatives for the PIMs most frequently reported. RESULTS: Fifty-eight tools reported 614 PIMs and 747 PIMs-interactions. Limited overlap between the tools was observed: 123 (69.1%) of 178 therapeutic alternatives proposed by the tools were considered inappropriate by other tools, and 222 (36.1%) of the 614 PIMs identified were named as being inappropriate only once. Only 21 tools were developed by a Delphi panel technique associated with systematic review. The PIMs listed as essential medication in Brazil and by the WHO were 30.6% and 23.3% of the total reported, respectively. For the most-cited PIMs, such as non-steroidal anti-inflammatory drugs, tricyclic antidepressants and benzodiazepines, we suggested the use of non-opioid and opioid analgesics; agomelatine, bupropion or moclobemide; and melatonin, respectively. CONCLUSIONS: The next stages in the development of explicit screening tools to identify PIMs include achieving more consensus between them and improving their applicability across countries. Further, it is recommended that tools include PIMs risks and advice on therapeutic alternatives.

Methodological standards for conducting and reporting meta-analyses: Ensuring the replicability of meta-analyses of pharmacist-led medication review.

BACKGROUND: Meta-analyses of clinical pharmacy services are frequently criticized for restricted data transparency and reproducibility. OBJECTIVES: To describe the methodological characteristics of meta-analyses of pharmacist-led medication reviews, to identify the elements that limit their replicability and robustness, and to propose recommendations for an appropriate conduction and reporting. METHODS: A meta-research study was conducted. Systematic searches of the PubMed, Scopus, and Web of Science databases were performed to identify meta-analyses of pharmacist services. Meta-analyses assessing the effect of pharmacist-led medication reviews were selected for data extraction, analysis and replication. Two replication exercises were performed for the two most common outcomes: (i) considering the data provided by authors to construct the meta-analysis and (ii) considering the raw data available in the primary studies included. Prediction intervals (PI), fragility index (FI), and number needed to treat (NNT) were also calculated for each replicated meta-analysis. RESULTS: Nine studies reporting meta-analyses about pharmacist-led medication review were found comprising 30 different outcomes. Eleven meta-analyses, including six for hospital admission and five for mortality, were replicated. In five meta-analyses, the pooled effect sizes of the replicated meta-analyses differed from the original ones. Only four meta-analyses mentioned the statistical method used. Other meta-analytic parameters (e.g., q-value, tau2) were omitted in all studies. In nine meta-analyses, the data from primary studies had been incorrectly extracted for at least one variable. The PI demonstrated that the uncertainty intervals of the effect sizes were always underestimated by the authors. NNTs showed wide intervals, ranging from benefit to harm, in almost all meta-analyses. Nine recommendations to facilitate the replication of a meta-analysis were proposed: providing all original data needed to build the analysis; informing about the imputed data or data obtained from different sources; performing sensitivity analyses for imputed or unpublished data; inform about all the statistical methods used; providing all statistical results; and reporting the PI, FI and NNT. CONCLUSION: Errors in data extraction and poor reporting of meta-analytic parameters are common in the pharmacy literature. We proposed nine recommendations to enhance data reproducibility and interpretability. Journal editors and peer reviewers should ensure that authors strictly comply with minimum standards for conduction and reporting of meta-analyses.

Methodological quality and risk of bias of meta-analyses of pharmacy services: A systematic review.

BACKGROUND: A suboptimal meta-analysis with misleading conclusions, frequently published in the healthcare journals, can compromise decision making in clinical practice. OBJECTIVE: To evaluate the reporting quality, methodological quality, and risk of bias of meta-analyses of pharmacy services. METHODS: Systematic searches to identify all the meta-analyses reporting the effect of pharmacy services were performed in PubMed, Scopus, and Web of Science. The reporting quality, the methodological quality, and the risk of bias of the included meta-analyses were evaluated using PRISMA checklist, R-AMSTAR, and ROBIS, respectively. RESULTS: A total of 109 meta-analyses were eligible for the study. The heterogeneity, the quality of evidence, and the quality analyses were poorly reported on authors' conclusions (14.3%, 14.7%, and 17.4%, respectively). The median scores of PRISMA and R-AMSTAR tolls were 24 (IQR 21.75-25), and 30 (IQR 27-32.5), respectively. Additionally, most of the studies were considered as high risk of bias (n = 83, 76.1%). No association between the date of publication and guideline compliance exists. PRISMA score was higher in studies published in high impact factor journals (rho = 0.313; p = 0.002), in articles that reported the quality of evidence obtained (p = 0.018), and in those that stated the need for future studies in their conclusions (p = 0.011). R-AMSTAR score was higher in studies published in high impact factor journals (rho = 0.338; p = 0.001), in those which reported the quality of evidence (p = 0.002), and in articles that described the quality analyses in their conclusions (p = 0.046). An association between the risk of bias and the recognition of the need for further studies in their conclusions (p = 0.041) was also found. CONCLUSION: The rapid increase of the meta-analyses of pharmacy services was not associated with higher quality. Mechanistic meta-analyses with poor conclusions are commonly published. Quality of the analyses, strength of evidence, heterogeneity, and absence of confrontation with current guidelines are rarely considered when synthetizing evidence and making recommendations.

Deficiency and Insufficiency of Vitamin D in Women of Childbearing Age: A Systematic Review and Meta-analysis.

OBJECTIVE: To estimate the prevalence of inadequate vitamin D level and its associated factors for women of childbearing age in Brazil. METHODS: A systematic review was conducted (last updated May 2020). Meta-analyses were performed using the inverse-variance for fixed models with summary proportion calculation by Freeman-Tukey double arcsine. Reporting and methodological quality were assessed using the Joanna Briggs Institute tool for prevalence studies. RESULTS: Our review identified 31 studies, comprising 4,006 participants. All the studies had at least one weakness, mainly due to the use of convenience sampling and small sample size. The overall prevalence of vitamin D deficiency, insufficiency, and both deficiency and insufficiency were 35% (confidence interval, 95%CI: 34-37%), 42% (95%CI: 41-44%), and 72% (95%CI: 71-74%), respectively. CONCLUSION: Although the magnitude of the prevalence of inadequate levels of vitamin D is uncertain, the evidence suggests that presence of vitamin D deficiency or insufficiency in women of reproductive age can cause moderate to severe problems.

OBJETIVO: Estimar a prevalência de níveis inadequados de vitamina D e seus fatores associados para mulheres em idade fértil no Brasil. MéTODOS: Uma revisão sistemática foi realizada (última atualização em maio de 2020). As meta-análises foram realizadas usando o inverso da variância para o modelo fixo com cálculo de proporção sumarizada por transformação arco-seno duplo de Freeman-Tukey. A qualidade metodológica e de reporte foi avaliada usando a ferramenta do Joanna Briggs Institute para estudos de prevalência. RESULTADOS: Nossa revisão identificou 31 estudos, compreendendo 4.006 participantes. Todos os estudos apresentaram pelo menos uma limitação, principalmente devido ao uso de amostra de conveniência e tamanho amostral pequeno. As prevalências gerais de deficiência, insuficiência e deficiência de vitamina D foram 35% (intervalo de confiança, IC 95%: 34­37%), 42% (IC 95%: 41­44%) e 72% (IC 95%: 71­74%), respectivamente. CONCLUSãO: Embora a magnitude da prevalência de níveis inadequados de vitamina D seja incerta, a evidência sugere que presença de deficiência ou insuficiência de vitamina D em mulheres em idade reprodutiva pode causar problemas moderados a graves.

Cost-Effectiveness of Molecular Method Diagnostic for Rapid Detection of Antibiotic-Resistant Bacteria.

OBJECTIVES: This study aimed to perform a cost-effectiveness analysis (CEA) of the molecular diagnostic method (MM) associated with conventional diagnostic method (CM) compared with the CM alone, for the detection of resistant profile in bacteremia, from the perspective of the Brazilian Public Health System, in intensive care units setting. METHODS: The clinical parameters regarding methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Gram-negative bacteria (CRGNB), and vancomycin-resistant Enterococcus spp. (VRE) infections were collected from searches on PubMed, Scopus, and SciELO, using specific keywords. Data on direct medical costs to treat these infections were collected according to Brazilian Public Health System perspective from Brazilian databases, in tables of 2018 to 2019. CEA was performed after building a dynamic model, which was calibrated and validated according to international recommendations. The incremental cost-effectiveness ratio of the MM + CM compared with the CM was calculated using the outcomes "avoided death" and "avoided resistant infections." One-way sensitivity analyses were performed. RESULTS: This CEA demonstrated that the MM + CM was dominant in all scenarios. Estimates showed that for MRSA, CRGNB, and VRE infections, every avoided death would lead to savings of Brazilian real (R$) 4.9 million ($937 301), R$2.2 million ($419 899), and R$1.3 million ($248 919), respectively. The same infections assessed by avoided resistant infections savings were projected to be R$24 964 ($4686), R$40 260 ($7558), and R$23 867 ($4480). CONCLUSIONS: MM leads to cost reduction and increased benefits, optimizing the use of financial resources on the health system in the intensive care unit setting, in bacteremia caused by MRSA, CRGNB, and VRE.

Hospitalization costs of coronaviruses diseases in upper-middle-income countries: A systematic review.

BACKGROUND: COVID-19, SARS and MERS are diseases that present an important health burden worldwide. This situation demands resource allocation to the healthcare system, affecting especially middle- and low-income countries. Thus, identifying the main cost drivers is relevant to optimize patient care and resource allocation. OBJECTIVE: To systematically identify and summarize the current status of knowledge on direct medical hospitalization costs of SARS, MERS, or COVID-19 in Upper-Middle-Income Countries. METHODS: We conducted a systematic review across seven key databases (PubMed, EMBASE, BVS Portal, CINAHL, CRD library, MedRxiv and Research Square) from database inception to February 2021. Costs extracted were converted into 2021 International Dollars using the Purchasing Power Parity-adjusted. The assessment of quality was based on the protocol by the BMJ and CHEERS. PROSPERO 2020: CRD42020225757. RESULTS: No eligible study about SARS or MERS was recovered. For COVID-19, five studies presented cost analysis performed in Brazil, China, Iran, and Turkey. Regarding total direct medical costs, the lowest cost per patient at ward was observed in Turkey ($900.08), while the highest in Brazil ($5,093.38). At ICU, the lowest was in Turkey ($2,984.78), while the highest was in China ($52,432.87). Service care was the most expressive (58% to 88%) cost driver of COVID-19 patients at ward. At ICU, there was no consensus between service care (54% to 87%) and treatment (72% to 81%) as key burdens of total cost. CONCLUSION: Our findings elucidate the importance of COVID-19 on health-economic outcomes. The marked heterogeneity among studies leaded to substantially different results and made challenging the comparison of data to estimate pooled results for single countries or regions. Further studies concerning cost estimates from standardized analysis may provide clearer data for a more substantial analysis. This may help care providers and policy makers to organize care for patients in the most efficient way.

Hydroxychloroquine versus placebo in the treatment of non-hospitalised patients with COVID-19 (COPE - Coalition V): A double-blind, multicentre, randomised, controlled trial.

Background: Previous Randomised controlled trials (RCT) evaluating chloroquine and hydroxychloroquine in non-hospitalised COVID-19 patients have found no significant difference in hospitalisation rates. However, low statistical power precluded definitive answers. Methods: We conducted a multicenter, double-blind, RCT in 56 Brazilian sites. Adults with suspected or confirmed COVID-19 presenting with mild or moderate symptoms with ≤ 07 days prior to enrollment and at least one risk factor for clinical deterioration were randomised (1:1) to receive hydroxychloroquine 400 mg twice a day (BID) in the first day, 400 mg once daily (OD) thereafter for a total of seven days, or matching placebo. The primary outcome was hospitalisation due to COVID-19 at 30 days, which was assessed by an adjudication committee masked to treatment allocation and following the intention-to-treat (ITT) principle. An additional analysis was performed only in participants with SARS-CoV-2 infection confirmed by molecular or serology testing (modified ITT [mITT] analysis). This trial was registered at ClinicalTrials.gov, NCT04466540. Findings: From May 12, 2020 to July 07, 2021, 1372 patients were randomly allocated to hydroxychloroquine or placebo. There was no significant difference in the risk of hospitalisation between hydroxychloroquine and placebo groups (44/689 [6·4%] and 57/683 [8·3%], RR 0·77 [95% CI 0·52-1·12], respectively, p=0·16), and similar results were found in the mITT analysis with 43/478 [9·0%] and 55/471 [11·7%] events, RR 0·77 [95% CI 0·53-1·12)], respectively, p=0·17. To further complement our data, we conducted a meta-analysis which suggested no significant benefit of hydroxychloroquine in reducing hospitalisation among patients with positive testing (69/1222 [5·6%], and 88/1186 [7·4%]; RR 0·77 [95% CI 0·57-1·04]). Interpretation: In outpatients with mild or moderate forms of COVID-19, the use of hydroxychloroquine did not reduce the risk of hospitalisation compared to the placebo control. Our findings do not support the routine use of hydroxychloroquine for treatment of COVID-19 in the outpatient setting. Funding: COALITION COVID-19 Brazil and EMS.

[Household storage and use of medications in a population served by the family health strategy in Brazil]. / Estoque doméstico e uso de medicamentos em uma população cadastrada na estratégia saúde da família no Brasil.

OBJECTIVE: To identify families served by the family health strategy (FHS) storing medicines at home, to evaluate storage conditions, and to investigate medicine use practices. METHODS: The study was conducted in a municipality in the state of São Paulo with two FHS units serving 1 867 households. The sample was selected by means of stratified random sampling. Data collection was conducted through semistructured interviews from July to October 2008. RESULTS: One resident was interviewed in each of the 280 households visited. Medicines were found in 255 households (91.1%). Of 326 storage locations, 217 (75.8%) were inadequate (easily accessible to children or exposed to moisture, light). Of the 2 578 medicines identified, 2 059 medicines (79.9%) in 236 (84.3%) households had safety or identification problems. Of the 280 respondents, 179 (63.9%) used medications. Of these, 24 were self-medicating, only one with an over-the-counter drug. Only 44 users had the prescription for their medication, and 21 did not follow the prescription in terms of dosage or had interrupted the treatment. CONCLUSIONS: Non-adherence to recommended treatment can lead to negative outcomes, such as inefficiency (using dosages lower than prescribed), poisoning (using dosages higher than prescribed), and other adverse reactions.

Drug interactions for elderly people with mental and behavioral disorders: a systematic scoping review.

OBJECTIVES: To identify drug interactions of potentially inappropriate medications and mental and behavioral disorders, according to explicit potentially inappropriate medications criteria-based tools. METHODOLOGY: A systematic scoping review was conducted in February 2020. Study characteristics, potentially inappropriate medications, drug interactions, rationale, and therapeutic management proposed were extracted. The commercialization and potentially inappropriate medications standard as essential in Brazil and in the world were identified. Therapeutic management was proposed for the most cited potentially inappropriate medications. RESULTS: 36 tools including 151 drug interactions, in addition to 132 potentially inappropriate medications with concerns related to six mental and behavioral disorders were identified. Cognitive impairment and dementia were the most frequently disorders reported and antipsychotics, anticholinergics, and benzodiazepines were the pharmacological classes more involved in the drug interactions. Despite the tools recommended risperidone and quetiapine when the use of antipsychotics were inevitable; levodopa + carbidopa for Parkinson's disease; and short and intermediate half-life benzodiazepines; the quality of the evidence needs to be assessed. In this review, sleep hygiene; deprescription; medication review; and clinical monitoring of adverse drug reactions are strongly recommended. In addition, to consider agomelatine, bupropion, moclobemide and melatonin as potential safer options for benzodiazepines. CONCLUSION: Knowing the clinical conditions or risk morbidities associated with the use of potentially inappropriate medications and management of these medications for safer therapeutic equivalents or non-pharmacotherapeutic alternatives are relevant for patient safety.

Analysis of completeness for spontaneous reporting of disease-modifying therapies in multiple sclerosis.

Introduction: Considering the need for effective postmarketing surveillance of disease-modifying therapies (DMTs) in multiple sclerosis (MS), we analyzed the potential of the spontaneous reports for safety signal detection, verifying the completeness of the reports in the FDA Adverse Event Reporting System (FAERS).Methods: All reports with DMTs for MS considered the primary suspect cause of ADRs and registered between January 2004 and June 2019 were selected. The vigiGrade completeness score was applied and reports with a score greater than 0.80 were considered well documented. Descriptive statistical analysis and comparisons of well-documented reports by DMTs were performed.Results: A total of 297,926 reports were analyzed. The lowest completeness rates were observed for type of report (13.5%), dose (62.7%), and time from treatment start to the ADR (79.0%). Overall, 80.8% of reports were classified as well documented and those related to natalizumab had the highest proportion (92.4%, p < 0.001), while the lowest was observed for reports sent in 2017 (53.1%, p < 0.001) and for teriflunomide (48.5%, p < 0.001).Conclusions: The high proportion of well-documented reports for DMTs indicates that they can be a valuable source for safety signal detection. A more careful analysis should be performed for data from the groups identified with low completeness to avoid the disclosure of spurious results.

Deficiency of vitamins C and E in women of childbearing age in Brazil: a systematic review and meta-analysis.

BACKGROUND: Despite the several options available for supplements containing vitamins C and E, evidence regarding the prevalence of deficiency or insufficiency of these vitamins is weak. OBJECTIVES: To estimate the prevalence of deficiency or insufficiency of vitamins C and E and associated factors among women of childbearing age, in Brazil. DESIGN AND SETTING: Systematic review and meta-analysis conducted at a Brazilian public university. METHODS: A search from index inception until May 2020 was conducted. Meta-analyses were performed using inverse variance for fixed models, with summary proportions calculation using Freeman-Tukey double arcsine (base case). Reporting and methodological quality were assessed using the Joanna Briggs Institute tool for prevalence studies. RESULTS: Our review identified 12 studies, comprising 1,316 participants, especially breastfeeding women. There was at least one quality weakness in all studies, mainly regarding sampling method (i.e. convenience sampling) and small sample size. The prevalence of vitamin C deficiency ranged from 0% to 40%. Only vitamin E deficiency was synthetized in meta-analyses, with mean prevalences of 6% regardless of the alpha-tocopherol cutoff in plasma, and 5% and 16% for cutoffs of < 1.6-12.0 mmol/l and < 16.2 mmol/l, respectively. The cumulative meta-analysis suggested that a trend to lower prevalence of vitamin E deficiency occurred in recent studies. CONCLUSIONS: Although the studies identified in this systematic review had poor methodological and reporting quality, mild-moderate vitamin C and E deficiencies were identified, especially in breastfeeding women. Thus, designing and implementing policies does not seem to be a priority, because the need has not been properly dimensioned among women of childbearing age in Brazil. REGISTRATION NUMBER IN PROSPERO: CRD42020221605.

Outcome measures for disease-modifying therapies in relapsing multiple sclerosis randomized clinical trials: a scoping review protocol.

OBJECTIVE: The objective of the review is to explore randomized controlled trials on disease-modifying therapies for relapsing multiple sclerosis to identify and quantify the different outcome measures, instruments and definitions of efficacy, safety outcomes, health-related quality of life instruments and population subgroups. INTRODUCTION: A wide range of therapies are available for relapsing multiple sclerosis, as well as a wide range of outcome measures and definitions, which can be explained by the absence of a core outcome set for this disease. Establishing a core outcome set is fundamental for guiding future studies as they improve the consistency and relevance of new findings and enable the results of trials to be compared and combined. These features are especially important for relapsing multiple sclerosis due to the limited number of head-to-head studies on this disease. Although many systematic reviews and meta-analyses have focused on the efficacy and safety of disease-modifying therapies in relapsing multiple sclerosis, none have had the specific objective of mapping outcome measures. INCLUSION CRITERIA: This review will consider randomized controlled trials that explore populational subgroups, efficacy, safety outcomes, health-related quality of life instruments and their definitions in the context of disease-modifying therapies for adults with relapsing multiple sclerosis. METHODS: Electronic searches will be performed in PubMed, Scopus, the Cochrane Library, ClinicalTrials.gov, and JBI Evidence Synthesis with no time limit. Two researchers will independently select registries (screening and eligibility steps) and extract data on study characteristics, outcome measures, definitions and population subgroups. Data will be presented in graphical or tabular form, accompanied by a narrative summary.