Clinical Equivalence between Generic Versus Branded Antibiotics: Systematic Review and Meta-Analysis.

Regulatory authorities authorize the clinical use of generic drugs (GD) based on bioequivalence studies, which consist of the evaluation of pharmacokinetics after a single dose in vitro or in healthy individuals. There are few data on clinical equivalence between generic and branded antibiotics. Our aim was to synthesize and analyze the available evidence on the clinical efficacy and safety of generic antibiotics compared to their original formulations. A systematic review was performed on Medline (PubMed) and Embase and validated through Epistemonikos and Google Scholar. The last search was conducted on 30 June 2022. Meta-analyses of clinical cure and mortality outcomes were performed. One randomized clinical trial (RCT) and 10 non-randomized intervention studies were included. No differences in clinical cure were observed between groups in the meta-analysis (OR = 0.89, 95% CI [0.61-1.28]; I2 = 70%, p = 0.005). No difference was observed between groups when considering the use of carbapenems for overall mortality (OR = 0.99, 95% CI [0.63-1.55]; I2 = 78%) or death associated with infections (OR = 0.79, 95% CI [0.48-1.29], I2 = 67%). Most of the studies were observational, and the duration of follow-up, the characteristics of the participants, and the sites of infections were heterogeneous. Due to the uncertainty of the evidence, it is not possible to contraindicate the use of generics, which is an important strategy to expand access.

Therapeutic Equivalence of Biosimilar and Reference Biologic Drugs in Rheumatoid Arthritis: A Systematic Review and Meta-analysis.

Importance: Biosimilar drugs are potentially lower-cost versions of biologics that may improve access to therapy. However, there is a lack of adequate systematic reviews demonstrating equivalence between these drugs for the treatment of rheumatoid arthritis (RA). Objectives: To assess the efficacy, safety, and immunogenicity associated with biosimilars of adalimumab, etanercept, and infliximab compared with their reference biologics in patients with RA. Data Sources: MEDLINE via PubMed, Embase, Cochrane Central Register of Controlled Trials, and LILACS databases were searched from inception to September 2021. Study Selection: Head-to-head randomized clinical trials (RCTs) of biosimilars of adalimumab, etanercept, and infliximab and their biologic reference drugs for RA were assessed. Data Extraction and Synthesis: Two authors independently abstracted all data. Meta-analysis was conducted with bayesian random effects using relative risks (RRs) for binary outcomes and standardized mean differences (SMDs) for continuous outcomes, with 95% credible intervals (CrIs) and trial sequential analysis. Specific domains were assessed for the risk of bias in equivalence and noninferiority trials. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Main Outcomes and Measures: Equivalence was tested using prespecified margins for the American College of Rheumatology criteria, with at least 20% improvement in the core set measures (ACR20) (ie, RR, 0.94 to 1.06), and for the Health Assessment Questionnaire-Disability Index (HAQ-DI) (ie, SMD, -0.22 to 0.22). Secondary outcomes included 14 items measuring safety and immunogenicity. Results: A total of 25 head-to-head trials provided data on 10 642 randomized patients with moderate to severe RA. Biosimilars met equivalence with reference biologics in terms of ACR20 response (24 RCTs with 10 259 patients; RR, 1.01; 95% CrI, 0.98 to 1.04; τ2 = 0.000) and change of HAQ-DI scores (14 RCTs with 5579 patients; SMD, -0.04; 95% CrI, -0.11 to 0.02; τ2 = 0.002) considering prespecified margins of equivalence. Trial sequential analysis found evidence for equivalence for ACR20 since 2017 and HAQ-DI since 2016. Overall, biosimilars were associated with similar safety and immunogenicity profiles compared with reference biologics. Conclusion and Relevance: In this systematic review and meta-analysis, biosimilars of adalimumab, infliximab, and etanercept were associated with clinically equivalent treatment effects compared with their reference biologics for the treatment of RA.

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.

Impact of switching between reference biologics and biosimilars of tumour necrosis factor inhibitors for rheumatoid arthritis: a systematic review and network meta-analysis.

What is the impact of switching between biologics and biosimilars of adalimumab, etanercept, and infliximab on efficacy and safety for rheumatoid arthritis? A systematic review and network meta-analysis were performed to compare switching and non-switching groups of treatments. Pooled Risk Relative (RR) or standardised mean differences (SMD) with 95% credible intervals (95% CrIs) were obtained. Seventeen randomized trials with a switching phase involving 6,562 patients were included. Results showed that a single switch from biologics to biosimilars compared to continuing biologics had comparable effects for primary and co-primary outcomes, the American College of Rheumatology criteria with 20% response (ACR20) (7 trials, 1,926 patients, RR 0.98, 95% CrIs 0.93 to 1.03) and the Health Assessment Questionnaire-Disability Index (HAQ-DI) (5 trials, 1,609 patients, SMD - 0.07, 95% CrIs - 0.23 to 0.1), and within the equivalence margins: ACR20 [RR 0.94, 1.06] and HAQ-DI [SMD - 0.22, 0.22]. The risk of treatment-emergent adverse events, discontinuation, and positive anti-drug antibodies were comparable after switching. Safety results were imprecise, and the follow-up period might not be sufficient to evaluate long-term effects, especially malignancies. Overall, the practice of single switching between approved biologics and biosimilars of Tumour Necrosis Factor inhibitors is efficacious and safe for rheumatoid arthritis.

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.

Application of ventilator-associated events (VAE) in ventilator-associated pneumonia (VAP) notified in Brazil (IMPACTO MR-PAV): a protocol for a cohort study.

INTRODUCTION: Certain criteria for ventilator-associated events (VAE) definition might influence the type of an event, its detection rate and consequently the resource expenditure in intensive care unit. The Impact of Infections by Antimicrobial-Resistant Microorganisms - Ventilator-Associated Pneumonia (IMPACTO MR-PAV) aims to evaluate the incidence and diagnostic accuracy of ventilator-associated pneumonia (VAP) using the current criteria for VAP surveillance in Brazil versus the VAE criteria defined by the US National Healthcare Safety Network-Center for Diseases Control and Prevention (CDC) criteria. METHODS AND ANALYSIS: The study will be conducted in around 15 centres across Brazil from October 2022 to December 2023. Trained healthcare professionals will collect data and compare the incidence of VAP using both the current criteria for VAP surveillance in Brazil and the VAE criteria defined by the CDC. The accuracy of the two criteria for identifying VAP will also be analysed. It will also characterise other events associated with mechanical ventilation (ventilator-associated condition, infection-related ventilator-associated complication) and adjudicate VAP reported to the Brazilian Health Regulatory Agency (ANVISA) using current epidemiological diagnostic criteria. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Board under the number 52354721.0.1001.0070. The study's primary outcome measure will be the incidence of VAP using the two different surveillance criteria, and the secondary outcome measures will be the accuracy of the two criteria for identifying VAP and the adjudication of VAP reported to ANVISA. The results will contribute to the improvement of VAP surveillance in Brazil and may have implications for other countries that use similar criteria. TRIAL REGISTRATION NUMBER: NCT05589727; Clinicaltrials.gov.

Rivaroxaban to prevent major clinical outcomes in non-hospitalised patients with COVID-19: the CARE - COALITION VIII randomised clinical trial.

Background: COVID-19 progression is associated with an increased risk of arterial and venous thrombosis. Randomised trials have demonstrated that anticoagulants reduce the risk of thromboembolism in hospitalised patients with COVID-19, but a benefit of routine anticoagulation has not been demonstrated in the outpatient setting. Methods: We conducted a randomised, open-label, controlled, multicentre study, evaluating the use of rivaroxaban in mild or moderate COVID-19 patients. Adults ≥18 years old, with probable or confirmed SARS-CoV-2 infection, presenting within ≤7 days from symptom onset with no clear indication for hospitalization, plus at least 2 risk factors for complication, were randomised 1:1 either to rivaroxaban 10 mg OD for 14 days or to routine care. The primary efficacy endpoint was the composite of venous thromboembolic events, need of mechanical ventilation, acute myocardial infarction, stroke, acute limb ischemia, or death due to COVID-19 during the first 30 days. ClinicalTrials.gov: NCT04757857. Findings: Enrollment was prematurely stopped due to sustained reduction in new COVID-19 cases. From September 29th, 2020, through May 23rd, 2022, 660 patients were randomised (median age 61 [Q1-Q3 47-69], 55.7% women). There was no significant difference between rivaroxaban and control in the primary efficacy endpoint (4.3% [14/327] vs 5.8% [19/330], RR 0.74; 95% CI: 0.38-1.46). There was no major bleeding in the control group and 1 in the rivaroxaban group. Interpretation: On light of these findings no decision can be made about the utility of rivaroxaban to improve outcomes in outpatients with COVID-19. Metanalyses data provide no evidence of a benefit of anticoagulant prophylaxis in outpatients with COVID-19. These findings were the result of an underpowered study, therefore should be interpreted with caution. Funding: COALITION COVID-19 Brazil and Bayer S.A.

Forecasting models for leprosy cases: a scoping review protocol.

INTRODUCTION: Leprosy is a neglected tropical disease caused by Mycobacterium leprae that mainly affects the skin, the peripheral nerves, the mucosa of the upper respiratory tract and the eyes. Mathematical models and statistical methodologies could play an important role in decision-making and help maintain the gains in elimination programmes. Various models for predicting leprosy cases have been reported in the literature, but they have different settings and distinct approaches to predicting the cases. This study describes the protocol for a scoping review to identify and synthesise information from studies using models to forecast leprosy cases. METHODS AND ANALYSIS: A scoping review methodology will be applied following the Joanna Briggs Institute methodology for scoping reviews and will be reported according to Preferred Reporting Items for Systematic Reviews and Meta-analysis Extension for Scoping Reviews. We will perform a systematic search from when each database started until April 2022 and we will include the following electronic databases: MEDLINE via PubMed, Embase, Cochrane Library and Latin American and Caribbean Health Science Literature Database. Data will be extracted and recorded on a calibrated predefined data form and will be presented in a tabular form accompanied by a descriptive summary. The Prediction Model Study Risk of Bias Assessment Tool (PROBAST) will be used. ETHICS AND DISSEMINATION: No ethical approval is required for this study. This scoping review will identify and map the methodological and other characteristics of modelling studies predicting leprosy cases. We hope that the review will contribute to scientific knowledge in this area and act as a basis for researchers designing and conducting leprosy models. This information can also be used to enhance national surveillance systems and to target specific policies. The protocol and consequent publications of this scoping review will be disseminated through peer-reviewed publications and policy briefs. SYSTEMATIC REVIEW REGISTRATION: This scoping review was registered in the Open Science Framework (https://doi.org/10.17605/OSF.IO/W9375).

Rationale and Design of the COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V) Randomized Clinical Trial: Hydroxychloroquine vs. Placebo in Non-Hospitalized Patients. / Justificativa e Desenho do Ensaio Clínico Randomizado COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V): Hidroxicloroquina vs. Placebo em Pacientes Não Hospitalizados.

BACKGROUND: Despite the need for targeting specific therapeutic options for coronavirus disease 2019 (COVID-19), there has been no evidence of effectiveness of any specific treatment for the outpatient clinical setting. There are few randomized studies evaluating hydroxychloroquine (HCQ) in non-hospitalized patients. These studies indicate no benefit from the use of HCQ, but they assessed different primary outcomes and presented important biases for outcome evaluation. OBJECTIVE: To evaluate if HCQ may prevent hospitalization due to COVID-19 compared to a matching placebo. METHODS: The COVID-19 Outpatient Prevention Evaluation (COPE) study is a pragmatic, randomized, double-blind, placebo-controlled clinical trial evaluating the use of HCQ (800 mg on day 1 and 400 mg from day 2 to day 7) or matching placebo for the prevention of hospitalization due to COVID-19 in early non-hospitalized confirmed or suspected cases. Inclusion criteria are adults (≥ 18 years) seeking medical care with mild symptoms of COVID-19, with randomization ≤ 7 days after symptom onset, without indication of hospitalization at study screening, and with at least one risk factor for complication (> 65 years; hypertension; diabetes mellitus; asthma; chronic obstructive pulmonary disease or other chronic lung diseases; smoking; immunosuppression; or obesity). All hypothesis tests will be two-sided. A p-value < 0.05 will be considered statistically significant in all analyses. Clinicaltrials.gov: NCT04466540. RESULTS: Clinical outcomes will be centrally adjudicated by an independent clinical event committee blinded to the assigned treatment groups. The primary efficacy endpoint will be assessed following the intention-to-treat principle. CONCLUSION: This study has the potential to reliably answer the scientific question of HCQ use in outpatients with COVID-19. To our knowledge, this is the largest trial evaluating HCQ in non-hospitalized individuals with COVID-19.

FUNDAMENTO: Apesar da necessidade de opções terapêuticas específicas para a doença do coronavírus 2019 (covid-19), ainda não há evidências da eficácia de tratamentos específicos no contexto ambulatorial. Há poucos estudos randomizados que avaliam a hidroxicloroquina (HCQ) em pacientes não hospitalizados. Esses estudos não indicaram benefício com o uso da HCQ; no entanto, avaliaram desfechos primários diferentes e apresentaram vieses importantes na avaliação dos desfechos. OBJETIVO: Investigar se a HCQ possui o potencial de prevenir hospitalizações por covid-19 quando comparada ao placebo correspondente. MÉTODOS: O estudo COVID-19 Outpatient Prevention Evaluation (COPE) é um ensaio clínico randomizado, pragmático, duplo-cego, multicêntrico e controlado por placebo que avalia o uso da HCQ (800 mg no dia 1 e 400 mg do dia 2 ao dia 7) ou placebo correspondente na prevenção de hospitalizações por covid-19 em casos precoces confirmados ou suspeitos de pacientes não hospitalizados. Os critérios de inclusão são adultos (≥ 18 anos) que procuraram atendimento médico com sintomas leves de covid-19, com randomização ≤ 7 dias após o início dos sintomas, sem indicação de hospitalização na triagem do estudo e com pelo menos um fator de risco para complicações (> 65 anos, hipertensão, diabetes melito, asma, doença pulmonar obstrutiva crônica ou outras doenças pulmonares crônicas, tabagismo, imunossupressão ou obesidade). Todos os testes de hipótese serão bilaterais. Um valor de p < 0,05 será considerado estatisticamente significativo em todas as análises. Clinicaltrials.gov: NCT04466540. RESULTADOS: Os desfechos clínicos serão avaliados centralmente por um comitê de eventos clínicos independente cegado para a alocação dos grupos de tratamento. O desfecho primário de eficácia será avaliado de acordo com o princípio da intenção de tratar. CONCLUSÃO: Este estudo apresenta o potencial de responder de forma confiável a questão científica do uso da HCQ em pacientes ambulatoriais com covid-19. Do nosso conhecimento, este é o maior estudo avaliando o uso de HCQ em indivíduos com covid-19 não hospitalizados.

Guidelines for the pharmacological treatment of COVID-19. The task-force/consensus guideline of the Brazilian Association of Intensive Care Medicine, the Brazilian Society of Infectious Diseases and the Brazilian Society of Pulmonology and Tisiology. / Diretrizes para o tratamento farmacológico da COVID-19. Consenso da Associação de Medicina Intensiva Brasileira, da Sociedade Brasileira de Infectologia e da Sociedade Brasileira de Pneumologia e Tisiologia.

INTRODUCTION: Different therapies are currently used, considered, or proposed for the treatment of COVID-19; for many of those therapies, no appropriate assessment of effectiveness and safety was performed. This document aims to provide scientifically available evidence-based information in a transparent interpretation, to subsidize decisions related to the pharmacological therapy of COVID-19 in Brazil. METHODS: A group of 27 experts and methodologists integrated a task-force formed by professionals from the Brazilian Association of Intensive Care Medicine (Associação de Medicina Intensiva Brasileira - AMIB), the Brazilian Society of Infectious Diseases (Sociedad Brasileira de Infectologia - SBI) and the Brazilian Society of Pulmonology and Tisiology (Sociedade Brasileira de Pneumologia e Tisiologia - SBPT). Rapid systematic reviews, updated on April 28, 2020, were conducted. The assessment of the quality of evidence and the development of recommendations followed the GRADE system. The recommendations were written on May 5, 8, and 13, 2020. RESULTS: Eleven recommendations were issued based on low or very-low level evidence. We do not recommend the routine use of hydroxychloroquine, chloroquine, azithromycin, lopinavir/ritonavir, corticosteroids, or tocilizumab for the treatment of COVID-19. Prophylactic heparin should be used in hospitalized patients, however, no anticoagulation should be provided for patients without a specific clinical indication. Antibiotics and oseltamivir should only be considered for patients with suspected bacterial or influenza coinfection, respectively. CONCLUSION: So far no pharmacological intervention was proven effective and safe to warrant its use in the routine treatment of COVID-19 patients; therefore such patients should ideally be treated in the context of clinical trials. The recommendations herein provided will be revised continuously aiming to capture newly generated evidence.

Rational use of diagnostic tests for clinical decision making.

OBJECTIVE: To assist clinicians to make adequate interpretation of scientific evidence from studies that evaluate diagnostic tests in order to allow their rational use in clinical practice. METHODS: This is a narrative review focused on the main concepts, study designs, the adequate interpretation of the diagnostic accuracy data, and making inferences about the impact of diagnostic testing in clinical practice. RESULTS: Most of the literature that evaluates the performance of diagnostic tests uses cross-sectional design. Randomized clinical trials, in which diagnostic strategies are compared, are scarce. Cross-sectional studies measure diagnostic accuracy outcomes that are considered indirect and insufficient to define the real benefit for patients. Among the accuracy outcomes, the positive and negative likelihood ratios are the most useful for clinical management. Variations in the study's cross-sectional design, which may add bias to the results, as well as other domains that contribute to decreasing the reliability of the findings, are discussed, as well as how to extrapolate such accuracy findings on impact and consequences considered important for the patient. Aspects of costs, time to obtain results, patients' preferences and values should preferably be considered in decision making. CONCLUSION: Knowing the methodology of diagnostic accuracy studies is fundamental, but not sufficient, for the rational use of diagnostic tests. There is a need to balance the desirable and undesirable consequences of tests results for the patients in order to favor a rational decision-making approach about which tests should be recommended in clinical practice.

The use of the o-arm® or radioscope in spine surgery: systematic review with meta-analysis / O uso do o-arm® ou da radioscopia em cirurgias da coluna: revisão sistemática com meta-análise / El uso de o-arm® o radioscopia en cirugías espinales: una revisión sistemática con metaanálisis

ABSTRACT The great advances in using new devices and imaging systems in surgeries aim to reproduce an ideal and safe scenario for the surgeon, the team, and the patient. New systems and devices are constantly available to demonstrate and facilitate intraoperative navigation, thereby reducing errors and avoiding complications for the patient and staff. This study evaluates and compares using the O-arm® system and radioscopy in the freehand technique in spine surgeries. For this, searches were conducted in PubMed and Embase for randomized and non-randomized studies using the O-arm® system and radioscopy in spine surgery. Twenty-four studies were included and compared regarding procedure time, accuracy of implant positioning, effective radiation dose, safety, and efficacy. In one study, the O-arm® group showed a shorter surgical time when compared to the freehand technique (222.5 min. [SD=38.0] vs. 255.2 min. [SD=40.3], p=0.011, respectively). In two studies, the freehand technique resulted in a lower effective radiation dose for patients. In 12 studies, a higher incidence of complications was observed among patients undergoing surgery with the freehand technique. It was concluded that using the O-arm® is associated with a reduction in malposition of implants and more safety for instrumented procedures. Still, no evidence exists that its use can result in less surgical time. Level of Evidence I; Diagnostic Analysis and Studies, Investigation of a Diagnostic Test.

Resumo: O grande avanço do uso de novos dispositivos e sistemas de imagem nas cirurgias tem por objetivo reproduzir um cenário ideal e seguro para o cirurgião, a equipe e o paciente. Constantemente, novos sistemas e aparelhos estão disponíveis para demonstrar e facilitar a navegação intraoperatória, com isso procurando reduzir erros e evitar complicações para o paciente e para equipe. Este estudo tem como objetivo avaliar e comparar o uso do sistema O-arm® e a utilização de radioescopia na técnica de freehand em cirurgias de coluna. Para isso, foram realizadas buscas nas bases PubMed e Embase de estudos randomizados e não randomizados sobre o uso em cirurgias de coluna do sistema O-arm® e radioscopia. Foram incluídos 24 estudos que foram comparados quanto ao tempo de procedimento, acurácia do posicionamento dos implantes, dose efetiva de radiação, segurança e eficácia. Um estudo o grupo O-arm® apresentou menor tempo cirúrgico quando comparado à técnica freehand (222,5 min. [DP=38,0] vs. 255,2 min. [DP=40,3], p=0,011, respectivamente). Em dois estudos, a técnica freehand resultou em menor dose efetiva de radiação para pacientes. Em 12 estudos observou-se maior incidência de complicações entre pacientes submetidos à cirurgia com técnica freehand. Concluiu-se que o uso do O-arm® está associado a uma redução da ocorrência do mal posicionamento dos implantes e mais segurança para os procedimentos instrumentados, porém sem evidências que seu uso possa resultar em menor tempo cirúrgico. Nível de Evidência I; Análises e Estudos Diagnósticos, Investigação de um Exame para Diagnóstico.

Resumen: El gran avance en el uso de nuevos dispositivos y sistemas de imagen en las cirugías pretende reproducir un escenario ideal y seguro para el cirujano, equipo y paciente. Constantemente se encuentran disponibles nuevos sistemas y dispositivos para demostrar y facilitar la navegación intraoperatoria, buscando así reducir errores y evitar complicaciones al paciente y al personal. Este estudio tiene como objetivo evaluar y comparar el uso del sistema O-arm® y el uso de radioscopia en la técnica de manos libres en cirugías de columna. Para ello se realizaron búsquedas en PubMed y Embase de estudios aleatorizados y no aleatorizados sobre el uso del sistema O-arm® y radioscopia. en cirugía de coluna. Se incluyeron y compararon 24 estudios con respecto al tiempo del procedimiento, precisión del posicionamiento del implante, dosis de radiación efectiva, seguridad y eficacia. En un estudio, el grupo O-arm® mostró tiempo quirúrgico más corto en comparación con técnica de mano alzada(222,5min [DE=38,0]vs. 255,2min[DE=40,3], p=0,011, respectivamente). En dos estudios, la técnica de mano alzada dio como resultado dosis de radiación efectiva más baja para los pacientes. En 12 estudios se observó mayor incidencia de complicaciones entre pacientes sometidos a cirugía con la técnica de mano alzada. Se concluyó que el uso del O-arm® está asociado con reducción en la ocurrencia de mala posición de los implantes y más seguridad para procedimientos instrumentados, pero sin evidencia de que su uso pueda resultar en menor tiempo quirúrgico. Descriptores:

Effectiveness and safety of anti-TNF in psoriatic arthritis patients in Brazil: a post-incorporation analysis.

AIM: Psoriatic arthritis is a chronic disease that can result in disability and decreased quality of life. MATERIALS & METHODS: A prospective cohort was conducted in Brazil. Disease activity was measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Clinical Disease Activity Index (CDAI), functionality by the Health Assessment Questionnaire Disability Index (HAQ-DI) and the quality of life by the EuroQol 5D (EQ-5D). RESULTS: In total, 122 patients were included. After 6 months, a median reduction of 2.03 in the BASDAI, 7.80 in the CDAI, 0.63 in the HAQ-DI and increase of 0.12 in the EQ-5D was observed. A good clinical response was observed in 45.5% of the patients by BASDAI and 54.5% by CDAI. Higher education and better quality of life were identified as predictors of effectiveness. The most common side effects were the infections. CONCLUSION: Anti-TNF-α drugs were effective and safe. The incorporation of them into the Brazilian Public Health System has provided therapeutic alternatives to the treatment of psoriatic arthritis.

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

Resumo 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.

Abstract 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.

Justificativa e Desenho do Ensaio Clínico Randomizado COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V): Hidroxicloroquina vs. Placebo em Pacientes Não Hospitalizados / Rationale and Design of the COVID-19 Outpatient Prevention Evaluation (COPE - Coalition V) Randomized Clinical Trial: Hydroxychloroquine vs. Placebo in Non-Hospitalized Patients

Resumo Fundamento Apesar da necessidade de opções terapêuticas específicas para a doença do coronavírus 2019 (covid-19), ainda não há evidências da eficácia de tratamentos específicos no contexto ambulatorial. Há poucos estudos randomizados que avaliam a hidroxicloroquina (HCQ) em pacientes não hospitalizados. Esses estudos não indicaram benefício com o uso da HCQ; no entanto, avaliaram desfechos primários diferentes e apresentaram vieses importantes na avaliação dos desfechos. Objetivo Investigar se a HCQ possui o potencial de prevenir hospitalizações por covid-19 quando comparada ao placebo correspondente. Métodos O estudo COVID-19 Outpatient Prevention Evaluation (COPE) é um ensaio clínico randomizado, pragmático, duplo-cego, multicêntrico e controlado por placebo que avalia o uso da HCQ (800 mg no dia 1 e 400 mg do dia 2 ao dia 7) ou placebo correspondente na prevenção de hospitalizações por covid-19 em casos precoces confirmados ou suspeitos de pacientes não hospitalizados. Os critérios de inclusão são adultos (≥ 18 anos) que procuraram atendimento médico com sintomas leves de covid-19, com randomização ≤ 7 dias após o início dos sintomas, sem indicação de hospitalização na triagem do estudo e com pelo menos um fator de risco para complicações (> 65 anos, hipertensão, diabetes melito, asma, doença pulmonar obstrutiva crônica ou outras doenças pulmonares crônicas, tabagismo, imunossupressão ou obesidade). Todos os testes de hipótese serão bilaterais. Um valor de p < 0,05 será considerado estatisticamente significativo em todas as análises. Clinicaltrials.gov: NCT04466540. Resultados Os desfechos clínicos serão avaliados centralmente por um comitê de eventos clínicos independente cegado para a alocação dos grupos de tratamento. O desfecho primário de eficácia será avaliado de acordo com o princípio da intenção de tratar. Conclusão Este estudo apresenta o potencial de responder de forma confiável a questão científica do uso da HCQ em pacientes ambulatoriais com covid-19. Do nosso conhecimento, este é o maior estudo avaliando o uso de HCQ em indivíduos com covid-19 não hospitalizados.

Abstract Background Despite the need for targeting specific therapeutic options for coronavirus disease 2019 (COVID-19), there has been no evidence of effectiveness of any specific treatment for the outpatient clinical setting. There are few randomized studies evaluating hydroxychloroquine (HCQ) in non-hospitalized patients. These studies indicate no benefit from the use of HCQ, but they assessed different primary outcomes and presented important biases for outcome evaluation. Objective To evaluate if HCQ may prevent hospitalization due to COVID-19 compared to a matching placebo. Methods The COVID-19 Outpatient Prevention Evaluation (COPE) study is a pragmatic, randomized, double-blind, placebo-controlled clinical trial evaluating the use of HCQ (800 mg on day 1 and 400 mg from day 2 to day 7) or matching placebo for the prevention of hospitalization due to COVID-19 in early non-hospitalized confirmed or suspected cases. Inclusion criteria are adults (≥ 18 years) seeking medical care with mild symptoms of COVID-19, with randomization ≤ 7 days after symptom onset, without indication of hospitalization at study screening, and with at least one risk factor for complication (> 65 years; hypertension; diabetes mellitus; asthma; chronic obstructive pulmonary disease or other chronic lung diseases; smoking; immunosuppression; or obesity). All hypothesis tests will be two-sided. A p-value < 0.05 will be considered statistically significant in all analyses. Clinicaltrials.gov: NCT04466540. Results Clinical outcomes will be centrally adjudicated by an independent clinical event committee blinded to the assigned treatment groups. The primary efficacy endpoint will be assessed following the intention-to-treat principle. Conclusion This study has the potential to reliably answer the scientific question of HCQ use in outpatients with COVID-19. To our knowledge, this is the largest trial evaluating HCQ in non-hospitalized individuals with COVID-19.

IMPACTO-MR: um estudo brasileiro de plataforma nacional para avaliar infecções e multirresistência em unidades de terapia intensiva / IMPACTO-MR: a Brazilian nationwide platform study to assess infections and multidrug resistance in intensive care units

RESUMO Objetivo: Descrever o IMPACTO-MR, um estudo brasileiro de plataforma nacional em unidades de terapia intensiva focado no impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. Métodos: Descrevemos a plataforma IMPACTO-MR, seu desenvolvimento, critérios para seleção das unidades de terapia intensiva, caracterização da coleta de dados, objetivos e projetos de pesquisa futuros a serem realizados na plataforma. Resultados: Os dados principais foram coletados por meio do Epimed Monitor System® e consistiram em dados demográficos, dados de comorbidades, estado funcional, escores clínicos, diagnóstico de internação e diagnósticos secundários, dados laboratoriais, clínicos e microbiológicos e suporte de órgãos durante a internação na unidade de terapia intensiva, entre outros. De outubro de 2019 a dezembro de 2020, 33.983 pacientes de 51 unidades de terapia intensiva foram incluídos no banco de dados principal. Conclusão: A plataforma IMPACTO-MR é um banco de dados clínico brasileiro de unidades de terapia intensiva focado na pesquisa do impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. Essa plataforma fornece dados para o desenvolvimento e pesquisa de unidades de terapia intensiva individuais e ensaios clínicos observacionais e prospectivos multicêntricos.

ABSTRACT Objective: To describe the IMPACTO-MR, a Brazilian nationwide intensive care unit platform study focused on the impact of health care-associated infections due to multidrug-resistant bacteria. Methods: We described the IMPACTO-MR platform, its development, criteria for intensive care unit selection, characterization of core data collection, objectives, and future research projects to be held within the platform. Results: The core data were collected using the Epimed Monitor System® and consisted of demographic data, comorbidity data, functional status, clinical scores, admission diagnosis and secondary diagnoses, laboratory, clinical, and microbiological data, and organ support during intensive care unit stay, among others. From October 2019 to December 2020, 33,983 patients from 51 intensive care units were included in the core database. Conclusion: The IMPACTO-MR platform is a nationwide Brazilian intensive care unit clinical database focused on researching the impact of health care-associated infections due to multidrug-resistant bacteria. This platform provides data for individual intensive care unit development and research and multicenter observational and prospective trials.

Comparative effectiveness of adalimumab and etanercept for rheumatoid arthritis in the Brazilian Public Health System.

AIM: Biological disease-modifying antirheumatic drugs (bDMARDs) are used to treat rheumatoid arthritis (RA) with adalimumab and etanercept the most used bDMARDs in Brazil. This open prospective cohort study evaluated their effectiveness and safety among RA patients in the Brazilian Public Health System given their costs. METHODS: The Clinical Disease Activity Index was primarily used to assess their effectiveness after 6 and 12 months of follow-up. The Health Assessment Questionnaire and EuroQol-5D were also used. RESULTS: A total of 266 RA patients started treatment with adalimumab or etanercept. Adalimumab was the most widely used bDMARD (70%). In total, 46% achieved remission or low-disease activity at 12 months with no difference in effectiveness between them (p = 0.306). bDMARDs were more effective in patients who had better functionality at treatment onset and had spent longer in education. CONCLUSION: This real-world study demonstrated that adalimumab and etanercept are equal alternatives for RA treatment and both were well tolerated.

Poorer functionality is related to better quality of life response following the use of biological drugs: 6-month outcomes in a prospective cohort from the Public Health System (Sistema Único de Saúde), Minas Gerais, Brazil.

We aim to analyze factors associated with the quality of life (QOL) response of individuals with rheumatic diseases treated by the Public Health System (Sistema Único de Saúde) with biological disease-modifying antirheumatic drugs (bDMARDs). Data from 428 patients using bDMARDs were collected using a standardized form at baseline and 6 months after the onset of treatment. The average reduction of the scores on EuroQol-five dimension was 0.11 ± 0.18 6 months after the onset of treatment with bDMARDs, denoting significant improvement of the participants' QOL. All the investigated types of disease exhibited significant improvement at the 6-month assessment, without any difference among them (p = 0.965). The participants with baseline poorest functionality and best QOL exhibited the best QOL outcomes after 6 months of treatment. Our study showed that the use of biological drugs induced considerable improvement in the participants' QOL.

Diretrizes para o tratamento farmacológico da COVID-19. Consenso da Associação de Medicina Intensiva Brasileira, da Sociedade Brasileira de Infectologia e da Sociedade Brasileira de Pneumologia e Tisiologia / Guidelines for the pharmacological treatment of COVID-19. The task-force/consensus guideline of the Brazilian Association of Intensive Care Medicine, the Brazilian Society of Infectious Diseases and the Brazilian Society of Pulmonology and Tisiology

RESUMO Introdução: Há diversas terapias sendo utilizadas, consideradas ou propostas para o tratamento da COVID-19, muitas carecendo de apropriada avaliação de efetividade e segurança. O propósito deste documento é fornecer recomendações baseadas nas evidências científicas disponíveis e em sua interpretação transparente, para subsidiar decisões sobre o tratamento farmacológico da COVID-19 no Brasil. Métodos: Um grupo de 27 especialistas e metodologistas integraram a força-tarefa formada pela Associação de Medicina Intensiva Brasileira (AMIB), pela Sociedade Brasileira de Infectologia (SBI) e pela Sociedade Brasileira de Pneumologia e Tisiologia (SBPT). Foram realizadas revisões sistemáticas rápidas, atualizadas até 28 de abril de 2020. A qualidade das evidências e a elaboração das recomendações seguiram o sistema GRADE. As recomendações foram elaboradas nos dias 5, 8 e 13 de maio de 2020. Resultados: Foram geradas 11 recomendações, embasadas em evidência de nível baixo ou muito baixo. Não há indicação para uso de rotina de hidroxicloroquina, cloroquina, azitromicina, lopinavir/ritonavir, corticosteroides ou tocilizumabe no tratamento da COVID-19. Heparina deve ser utilizada em doses profiláticas no paciente hospitalizado, mas não deve ser realizada anticoagulação na ausência de indicação clínica específica. Antibacterianos e oseltamivir devem ser considerados somente nos pacientes em suspeita de coinfecção bacteriana ou por influenza, respectivamente. Conclusão: Até o momento, não há intervenções farmacológicas com efetividade e segurança comprovada que justifiquem seu uso de rotina no tratamento da COVID-19, devendo os pacientes serem tratados preferencialmente no contexto de pesquisa clínica. As recomendações serão revisadas continuamente, de forma a capturar a geração de novas evidências.

ABSTRACT Introduction: Different therapies are currently used, considered, or proposed for the treatment of COVID-19; for many of those therapies, no appropriate assessment of effectiveness and safety was performed. This document aims to provide scientifically available evidence-based information in a transparent interpretation, to subsidize decisions related to the pharmacological therapy of COVID-19 in Brazil. Methods: A group of 27 experts and methodologists integrated a task-force formed by professionals from the Brazilian Association of Intensive Care Medicine (Associação de Medicina Intensiva Brasileira - AMIB), the Brazilian Society of Infectious Diseases (Sociedad Brasileira de Infectologia - SBI) and the Brazilian Society of Pulmonology and Tisiology (Sociedade Brasileira de Pneumologia e Tisiologia - SBPT). Rapid systematic reviews, updated on April 28, 2020, were conducted. The assessment of the quality of evidence and the development of recommendations followed the GRADE system. The recommendations were written on May 5, 8, and 13, 2020. Results: Eleven recommendations were issued based on low or very-low level evidence. We do not recommend the routine use of hydroxychloroquine, chloroquine, azithromycin, lopinavir/ritonavir, corticosteroids, or tocilizumab for the treatment of COVID-19. Prophylactic heparin should be used in hospitalized patients, however, no anticoagulation should be provided for patients without a specific clinical indication. Antibiotics and oseltamivir should only be considered for patients with suspected bacterial or influenza coinfection, respectively. Conclusion: So far no pharmacological intervention was proven effective and safe to warrant its use in the routine treatment of COVID-19 patients; therefore such patients should ideally be treated in the context of clinical trials. The recommendations herein provided will be revised continuously aiming to capture newly generated evidence.