Real-World Evidence of Ribociclib Plus Aromatase Inhibitors as First-Line Treatment in Advanced Breast Cancer: The BrasiLEEira Study.

PURPOSE: Cyclin inhibitors plus endocrine therapy represent the reference standard for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer (ABC). Efficacy results on hard end points such as overall survival come from well-designed randomized clinical trials (RCTs). However, a limitation of RCTs is the low external results validity, and their extrapolation to a broader population may not be appropriate. Real-world studies can overcome these limitations, also increasing the reliability of RCTs. MATERIALS AND METHODS: The BrasiLEEira was an observational, longitudinal, retrospective, multicenter study to evaluate the effectiveness and safety of ribociclib plus nonsteroidal aromatase inhibitors in Brazilian women age 18 years or older with HR+/HER2- ABC. The study was approved by the institutional review boards of all 11 hospitals. Data were collected anonymously from medical records using an electronic case report form designed by an independent academic research organization, which conducted the study considering all recommendations of international guidelines. The primary end point was 1-year progression-free survival (PFS) rate. Secondary end points included mortality, dose reduction, and safety. RESULTS: The mean age of 76 patients was 57 years, and 28.9% were Black/Brown. The most prevalent comorbidity was arterial hypertension (34.7%). About 26.0% had endocrine-resistant disease, and 54.1% had more than three metastatic sites. The PFS rate was 77.6%. Three patients died (3.9%). Dose reductions occurred in 37.7% of patients. The most common adverse event was neutropenia (68.4%). CONCLUSION: The high-quality evidence from the BrasiLEEira study corroborates the RCTs' findings, expanding its validity to a broader spectrum and underrepresented population who may benefit from ribociclib treatment.

Effect of ribociclib on productivity losses due to breast cancer in young women in Brazil.

OBJETIVE: To evaluate the effect of ribociclib versus endocrine therapy on productivity losses due to advanced breast cancer. METHODS: Productivity data from the MONALEESA-7 trial, obtained from the results of the application of the Work Productivity and Activity Impairment (WPAI) questionnaire on progression-free survival state (43-month follow-up), were extrapolated to the 10,936 Brazilian prevalent cases of premenopausal women with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer. Productivity loss was determined by quantifying the economic costs of workforce dropout over time in both treatment arms and by discounting the economic costs of absenteeism and presenteeism from workforce retention. A human capital approach was used. RESULTS: Net productivity gains in the ribociclib arm were estimated at USD 4,285,525.00, representing 316,609 added work hours over 43 months and a mean of 2,009 added work weeks per year. CONCLUSIONS: The phase III MONALEESA-7 trial productivity results applied to the Brazilian premenopausal prevalent cases of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer showed that treatment with ribociclib + endocrine therapy improves workforce participation compared with endocrine therapy alone in premenopausal women with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer, with potential economic gains for the Brazilian society.

Cost-effectiveness of ribociclib for premenopausal or perimenopausal women with HR+/HER2- advanced breast cancer: a Brazilian public health care system perspective.

Introduction: The MONALEESA-7 trial compared ribociclib plus endocrine therapy (ET) with placebo as first-line treatment of advanced luminal/HER2-negative breast cancer (ABC) in premenopausal and perimenopausal women (age <50 years) and showed significant benefits to progression-free survival and overall survival. This study aimed to compare the cost-effectiveness of ribociclib + ET versus ET alone in patients with ABC from the perspective of the Brazilian public national health system. Methods: We calculated the incremental cost-effectiveness ratio (ICER) using a Markov model with progression-free survival, post-progression survival, and death states. We expressed ICER as incremental costs per progression-free life-year (PFLY) and quality-adjusted life-year (QALY) gained in a 10-year time horizon. We used parametric survival distributions fit to MONALEESA-7 data to generate survival distributions for progression-free and post-progression survival. The largest British preference study in breast cancer served as the basis to estimate health-state utilities. We estimated direct costs (ABC treatment, follow-up, monitoring, and adverse events) using Brazilian-specific values from public sources. An expert consensus panel determined the resource patterns required. We applied annual discounts of 5% to costs and QALYs. Results: Ribociclib + ET resulted in an incremental gain of 1.03 PFLYs and 0.80 QALYs at a cost of $37,319.31. The ICER of ribociclib + ET versus ET was $36,379.41 per PFLY gained and $46,590.79 per QALY gained. In deterministic sensitivity analysis, results were primarily affected by the annual discount rate, followed by the cost of ribociclib. In probabilistic sensitivity analysis, simulations agreed with the base-case. Conclusion: Ribociclib increased PFLYs and QALYs in patients with HR+/HER2- ABC when added to ET. Because Brazil does not have a formally defined cost-effectiveness threshold, other domains need to be considered for incorporation decisions, such as disease burden and humanistic impact on this young, economically active population. These findings may be useful in discussions for incorporation of ribociclib into the Brazilian public health system.

Effect of ribociclib on productivity losses due to breast cancer in young women in Brazil

ABSTRACT OBJETIVE To evaluate the effect of ribociclib versus endocrine therapy on productivity losses due to advanced breast cancer. METHODS Productivity data from the MONALEESA-7 trial, obtained from the results of the application of the Work Productivity and Activity Impairment (WPAI) questionnaire on progression-free survival state (43-month follow-up), were extrapolated to the 10,936 Brazilian prevalent cases of premenopausal women with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer. Productivity loss was determined by quantifying the economic costs of workforce dropout over time in both treatment arms and by discounting the economic costs of absenteeism and presenteeism from workforce retention. A human capital approach was used. RESULTS Net productivity gains in the ribociclib arm were estimated at USD 4,285,525.00, representing 316,609 added work hours over 43 months and a mean of 2,009 added work weeks per year. CONCLUSIONS The phase III MONALEESA-7 trial productivity results applied to the Brazilian premenopausal prevalent cases of hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer showed that treatment with ribociclib + endocrine therapy improves workforce participation compared with endocrine therapy alone in premenopausal women with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer, with potential economic gains for the Brazilian society.

Cost-effectiveness of ribociclib plus letrozole versus palbociclib plus letrozole or letrozole as monotherapy in first-line treatment of postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer: a Brazilian private payer perspective.

BACKGROUND: The global burden of breast cancer (BC) is high, especially in advanced stages. CDK 4/6 inhibitors represent a paradigm shift in the treatment of advanced BC HR+/HER2-, given the clinically and statistically significant gain in overall survival associated with this new class of medications. Nevertheless, as an innovation, the incorporation of these drugs impacts healthcare budgets, requiring cost-effectiveness analyses for decision-making. The aim of this study was to evaluate the cost-effectiveness of ribociclib plus letrozole compared with palbociclib plus letrozole or letrozole as monotherapy for first-line treatment of postmenopausal women with HR+/HER2- locally advanced or metastatic BC (aBC) from a Brazilian private healthcare system perspective. METHODS: A model including progression-free survival (PFS), progressed disease, and death health states was used to simulate lifetime costs and outcomes. PFS and overall survival were derived from the MONALEESA-2 trial (lifetime horizon). Healthcare costs included drug acquisition and monitoring, subsequent therapies, adverse events, and end-of-life costs. Effectiveness was measured in quality-adjusted life-years (QALYs). Deterministic and probabilistic sensitivity analyses were performed. RESULTS: The total cost of treatment with ribociclib plus letrozole was USD 72,091.82 versus USD 92,749.64 for palbociclib plus letrozole. Total QALYs were 3.30 and 3.16, respectively. Base-case analysis showed ribociclib as dominant over palbociclib in first-line treatment of women with HR+/HER2- aBC, associated with cost savings and QALY gains. The total cost of treatment with ribociclib plus letrozole was USD 83,058.73 versus USD 29,215.10 for letrozole. Total QALYs were 3.84 and 2.61, respectively. Compared with letrozole, ribociclib plus letrozole was associated with an incremental cost of USD 53,843.64 and an incremental QALY gain of 1.23, with incremental cost-effectiveness ratio of USD 43,826.91 per QALY gained. CONCLUSIONS: As demonstrated by the cost-effectiveness dominance over palbociclib, ribociclib results in savings when used as first-line treatment in postmenopausal women with HR+/HER2- aBC, warranting incorporation in the private healthcare system.

Clinical practice guidelines in Brazil - developing a national programme.

In Brazil, governmental and non-governmental organisations develop practice guidelines (PGs) in order to optimise patient care. Although important improvements have been made over the past years, many of these documents still lack transparency and methodological rigour. In order to conduct a critical analysis and define future steps in PG development in Brazil, we carried out a structured assessment of strengths, weaknesses, opportunities and threats (SWOT analysis) for the development of a national guideline programme. Participants consisted of academia, methodologists, medical societies and healthcare system representatives. In summary, the PG development process has improved in Brazil and current investments in methodological research and capacity-building are ongoing. Despite the centralised processes for public PGs, standardised procedures for their development are not well established and human resources are insufficient in number and capacity to develop the amount of trustworthy documents needed. Brazil's capacity could be strengthened and initial efforts have been made such as the adoption of standards proposed by world-renowned institutions in PG development and enhancement of the involvement of key stakeholders. Further steps involve the alignment between health technology assessment and PG processes for synergy and the development of a national network to promote the interaction between groups involved in the development of PGs. The lessons learned from this paper could be used to foster debate on guideline development, especially for countries facing similar threats on this topic.

Can Enhanced Techniques Improve the Diagnostic Accuracy of Transvaginal Sonography and Magnetic Resonance Imaging for Rectosigmoid Endometriosis? A Systematic Review and Meta-analysis.

OBJECTIVE: Our aim was to perform a systematic review and meta-analysis of the most commonly used examinations for rectosigmoid lesions of deeply infiltrating endometriosis, transvaginal sonography (TVS) and magnetic resonance imaging (MRI), to compare their diagnostic accuracy and enhanced or non-enhanced techniques. METHODS: A systematic search was performed until March 2018 without time or language restrictions. Eligibility criteria included studies that compared the accuracy of TVS and MRI for diagnosis of rectosigmoid endometriosis. The quality of the studies was assessed by means of Quality Assessment of Diagnostic Accuracy Studies-2 and Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. Bivariate and hierarchical analysis were performed. The difference in the accuracy of TVS and MRI was tested, and heterogeneity was addressed by means of meta-regression, sensitivity, or subgroup analysis. RESULTS: A total of 1754 studies were screened; 105 studies were eligible, and 11 studies were included in the meta-analysis. Overall pooled sensitivity, specificity, and area under the receiver operating characteristic curve were 0.80, 0.94, and 0.95, respectively. The measures for MRI were 0.82, 0.94, and 0.95, respectively. There was no statistical difference between the accuracy values of TVS and MRI (P = 0.90). The use of bowel preparation and vaginal contrast could enhance the accuracy of MRI. Along with rectosigmoid prevalence, bowel and vaginal contrast explained a significant proportion of the statistical heterogeneity. CONCLUSIONS: Both TVS and MRI showed high diagnostic accuracy for rectosigmoid deeply infiltrating endometriosis lesions. There is no strong evidence suggesting that the two diagnostic methods might differ in specificity or sensitivity, but enhanced techniques may increase the accuracy measures.

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.

Comparison of Biological and Mechanical Prostheses for Heart Valve Surgery: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: The choice of a mechanical (MP) or biological prosthesis (BP) for patients with valvular heart disease undergoing replacement is still not a consensus. OBJECTIVE: We aimed to determine the clinical outcomes of MP or BP placement in those patients. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared biological prostheses and mechanical prostheses in patients with valvular heart diseases and assessed the outcomes. RCTs were searched in the MEDLINE, EMBASE, LILACS, CENTRAL, SCOPUS and Web of Science (from inception to November 2014) databases. Meta-analyses were performed using inverse variance with random effects models. The GRADE system was used to rate the quality of the evidence. A P-value lower than 0.05 was considered significant. RESULTS: A total of four RCTs were included in the meta-analyses (1,528 patients) with follow up ranging from 2 to 20 years. Three used old generation mechanical and biological prostheses, and one used contemporary prostheses. No significant difference in mortality was found between BP and MP patients (risk ratio (RR = 1.07; 95% CI 0.99-1.15). The risk of bleeding was significantly lower in BP patients than MP patients (RR = 0.64; 95% CI 0.52-0.78); however, reoperations were significantly more frequent in BP patients (RR = 3.60; 95% CI 2.44-5.32). There were no statistically significant differences between BP and MP patients with respect to systemic arterial embolisms and infective endocarditis (RR = 0.93; 95% CI 0.66-1.31, RR = 1.21; CI95% 0.78-1.88, respectively). Results in the trials with modern and old prostheses were similar. CONCLUSIONS: The mortality rate and the risk of thromboembolic events and endocarditis were similar between BP and MP patients. The risk of bleeding was approximately one third lower for BP patients than for MP patients, while the risk of reoperations was more than three times higher for BP patients.

Rational use of diagnostic tests for clinical decision making

SUMMARY 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.

RESUMO OBJETIVO: Auxiliar os clínicos na interpretação adequada das evidências científicas de estudos que avaliam testes diagnósticos, de modo a permitir seu uso racional na prática clínica. MÉTODOS: Revisão narrativa da literatura dos principais conceitos, desenhos de estudo, interpretação adequada dos dados de acurácia diagnóstica e realização de inferências sobre o impacto do teste diagnóstico na prática clínica. RESULTADOS: A maioria da literatura que avalia o desempenho de testes diagnósticos utiliza como delineamento os estudos transversais. Ensaios clínicos randomizados, avaliando desfechos clínicos, que seriam considerados ideais, são escassos. Os estudos transversais mensuram desfechos de acurácia diagnóstica que são considerados indiretos e insuficientes para definir o real benefício para os pacientes. Dentre os desfechos, as razões de verossimilhança positiva e negativa são as mais úteis para a decisão da conduta clínica. Variações no delineamento transversal do estudo, que podem acrescentar vieses aos resultados, bem como outros domínios que contribuem para diminuir a confiabilidade dos achados, são discutidos, além de como extrapolar tais achados de acurácia em impacto e consequências consideradas importantes para o paciente. Aspectos sobre custos, tempo para a obtenção do resultado, preferências e valores dos pacientes devem, preferencialmente, participar da tomada de decisão. CONCLUSÃO: Conhecer a metodologia dos estudos de acurácia diagnóstica é fundamental, porém não suficiente, para o uso racional de testes diagnósticos. Há a necessidade de se ponderarem as consequências desejáveis e indesejáveis dos resultados dos testes para os pacientes, de modo a favorecer a tomada de decisão racional acerca de qual teste recomendar na prática clínica.

Comparison of Biological and Mechanical Prostheses for Heart Valve Surgery: A Systematic Review of Randomized Controlled Trials / Comparação de Próteses Biológicas e Mecânicas para Cirurgia de Válvula Cardíaca: Revisão Sistemática de Estudos Controlados Randomizados

Abstract Background: The choice of a mechanical (MP) or biological prosthesis (BP) for patients with valvular heart disease undergoing replacement is still not a consensus. Objective: We aimed to determine the clinical outcomes of MP or BP placement in those patients. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared biological prostheses and mechanical prostheses in patients with valvular heart diseases and assessed the outcomes. RCTs were searched in the MEDLINE, EMBASE, LILACS, CENTRAL, SCOPUS and Web of Science (from inception to November 2014) databases. Meta-analyses were performed using inverse variance with random effects models. The GRADE system was used to rate the quality of the evidence. A P-value lower than 0.05 was considered significant. Results: A total of four RCTs were included in the meta-analyses (1,528 patients) with follow up ranging from 2 to 20 years. Three used old generation mechanical and biological prostheses, and one used contemporary prostheses. No significant difference in mortality was found between BP and MP patients (risk ratio (RR = 1.07; 95% CI 0.99-1.15). The risk of bleeding was significantly lower in BP patients than MP patients (RR = 0.64; 95% CI 0.52-0.78); however, reoperations were significantly more frequent in BP patients (RR = 3.60; 95% CI 2.44-5.32). There were no statistically significant differences between BP and MP patients with respect to systemic arterial embolisms and infective endocarditis (RR = 0.93; 95% CI 0.66-1.31, RR = 1.21; CI95% 0.78-1.88, respectively). Results in the trials with modern and old prostheses were similar. Conclusions: The mortality rate and the risk of thromboembolic events and endocarditis were similar between BP and MP patients. The risk of bleeding was approximately one third lower for BP patients than for MP patients, while the risk of reoperations was more than three times higher for BP patients.

Resumo Fundamento: A escolha de próteses mecânicas ou biológicas para pacientes com doença de válvula cardíaca ainda não é um consenso. Objetivo: Determinar os desfechos clínicos de próteses mecânicas e biológicas nesses pacientes. Métodos: Conduzimos uma revisão sistemática e metanálise e estudos controlados randomizados (RCTs) que compararam próteses mecânicas e biológicas em pacientes com doenças de válvulas cardíaca, e avaliamos seus resultados. A busca por RCTs foi feita nas bases de dados MEDLINE, EMBASE, LILACS, CENTRAL, SCOPUS e Web of Science (do início a novembro de 2014). As metanálises foram realizadas usando variação inversa com modelos de efeitos aleatórios. Usamos o sistema GRADE para avaliar a qualidade da evidência. Um valor menor que 0,05 foi considerado significativo. Resultados: Um total de quatro RCTs foi incluído na metanálise (1528 pacientes) com acompanhamento de 2 a 20 anos. Em três estudos, foram utilizadas próteses mecânicas e biológicas mais antigas, e em um estudo próteses contemporâneas. Não foi observada diferença de mortalidade entre os pacientes que receberam próteses mecânicas e biológicas (risco relativo, RR = 1,07; IC95% 0,99-1,15). O risco de sangramento foi significativamente mais baixo nos pacientes que receberam próteses biológicas que naqueles com próteses mecânicas (RR = 0,64; IC95% 0,52-0,78). Contudo, as reoparações foram mais frequentes em pacientes com próteses biológicas (RR = 3,60; IC95% 2,44-5,32). Não houve diferenças estatisticamente significativas entre pacientes com próteses biológicas e mecânicas em relação à embolia arterial sistêmica e endocardite infecciosa (RR = 0,93; IC95% 0,66-1,31; RR = 1,21; IC95% 0,78-1,88, respectivamente). Resultados entre os estudos com próteses modernas e antigas foram similares. Conclusões: A taxa de mortalidade e o risco de eventos tromboembólicos e endocardite foram similares entre os pacientes que receberam próteses biológicas e mecânicas. O risco de sangramentos foi aproximadamente um terço menor nos pacientes com próteses biológicas que mecânicas, ao passo que o risco de reoperação foi mais que três vezes maior nos pacientes com próteses biológicas.

The Overt and Hidden Use of Animal-Derived Products in Alternative Methods for Skin Sensitisation: A Systematic Review.

In vitro methods that can replace animal testing in the identification of skin sensitisers are now a reality. However, as cell culture and related techniques usually rely on animal-derived products, these methods may be failing to address the complete replacement of animals in safety assessment. The objective of this study was to identify the animal-derived products that are used as part of in vitro methods for skin sensitisation testing. Thus, a systematic review of 156 articles featuring 83 different in vitro methods was carried out and, from this review, the use of several animal-derived products from different species was identified, with the use of fetal bovine serum being cited in most of the methods (78%). The use of sera from other animals, monoclonal antibodies and animal proteins were also variously mentioned. While non-animal alternatives are available and methods free of animal-derived products are emerging, most of the current methods reported used at least one animal-derived product, which raises ethical and technical concerns. Therefore, to deliver technically and ethically better in vitro methods for the safety assessment of chemicals, more effort should be made to replace products of animal origin in existing methods and to avoid their use in the development of new method protocols.

Viscosupplementation for Hip Osteoarthritis: A Systematic Review and Meta-Analysis of the Efficacy on Pain and Disability, and the Occurrence of Adverse Events.

OBJECTIVE: To assess the efficacy of viscosupplementation (hyaluronic acid [HA]) on the pain and disability caused by hip osteoarthritis, and to determine the occurrence of adverse events. DATA SOURCES: PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov database, and specific journals up to March 2017. STUDY SELECTION: Randomized controlled trials (RCTs) comparing HA with any other intra-articular injection. DATA EXTRACTION: Performed according to Cochrane/Grades of Recommendation, Assessment, Development, and Evaluation criteria. Two authors extracted data and assessed the risk of bias and quality of evidence. A random-effects meta-analysis was conducted. DATA SYNTHESIS: Eight RCTs were retrieved (n=807): 4 comparing HA to placebo; 3 to platelet-rich plasma (PRP); 3 to methylprednisolone; and 1 to mepivacaine. Some RCTs had 3 arms. There is very low evidence that HA is not superior to placebo for pain at 3 months (standardized mean difference [SMD]=-.06; 95% CI, -.38 to .25; P=.69), and high evidence that it is not superior in adverse events (risk ratio [RR]=1.21; 95% CI, .79-1.86; P=.38). There is low evidence that HA is not superior to PRP for pain at 1 month. There is very low evidence that HA is not superior to PRP for pain at 6 and 12 months (mean difference in visual analog scale [in cm]: -.05 [95% CI, -.81 to .71], 1.0 [95% CI, -1.5 to 3.50], and .81 [95% CI, -1.11 to 2.73], respectively). There is high evidence that HA is no different from methylprednisolone for pain at 1 month (SMD=.02; 95% CI, -.18 to .22; P=.85). There is low evidence that HA is no different from methylprednisolone for Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International Responders Index at 1 month (RR=.44; 95% CI, .10-1.95; P=.28). There is high evidence that HA is no different from methylprednisolone for adverse events (RR=1.21; 95% CI, .79-1.87; P=.38). CONCLUSIONS: We do not recommend viscosupplementation for hip osteoarthritis. Compared with placebo, data show scarce evidence of its efficacy up to 3 months, and suggest no difference at 6 months. However, future RCTs could present HA as an alternative to methylprednisolone for short-term symptom relief.

Long-acting muscarinic antagonists vs. long-acting ß 2 agonists in COPD exacerbations: a systematic review and meta-analysis.

OBJECTIVE: To determine whether long-acting muscarinic antagonists (LAMAs) provide superior therapeutic effects over long-acting ß2 agonists (LABAs) for preventing COPD exacerbations. METHODS: This was a systematic review and meta-analysis of randomized clinical trials involving patients with stable, moderate to severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease criteria, treated with a LAMA (i.e., tiotropium bromide, aclidinium, or glycopyrronium), followed for at least 12 weeks and compared with controls using a LABA in isolation or in combination with a corticosteroid. RESULTS: A total of 2,622 studies were analyzed for possible inclusion on the basis of their title and abstract; 9 studies (17,120 participants) were included in the analysis. In comparison with LABAs, LAMAs led to a greater decrease in the exacerbation rate ratio (relative risk [RR] = 0.88; 95% CI: 0.84-0.93]; a lower proportion of patients who experienced at least one exacerbation (RR = 0.90; 95% CI: 0.87-0.94; p < 0.00001); a lower risk of exacerbation-related hospitalizations (RR = 0.78; 95% CI: 0.69-0.87; p < 0.0001); and a lower number of serious adverse events (RR = 0.81; 95% CI: 0.67-0.96; p = 0.0002). The overall quality of evidence was moderate for all outcomes. CONCLUSIONS: The major findings of this systematic review and meta-analysis were that LAMAs significantly reduced the exacerbation rate (exacerbation episodes/year), as well as the number of exacerbation episodes, of hospitalizations, and of serious adverse events.

Long-acting muscarinic antagonists vs. long-acting β 2 agonists in COPD exacerbations: a systematic review and meta-analysis / Antagonistas muscarínicos de longa duração vs. β 2 -agonistas de longa duração em exacerbações da DPOC: revisão sistemática e meta-análise

ABSTRACT Objective: To determine whether long-acting muscarinic antagonists (LAMAs) provide superior therapeutic effects over long-acting β2 agonists (LABAs) for preventing COPD exacerbations. Methods: This was a systematic review and meta-analysis of randomized clinical trials involving patients with stable, moderate to severe COPD according to the Global Initiative for Chronic Obstructive Lung Disease criteria, treated with a LAMA (i.e., tiotropium bromide, aclidinium, or glycopyrronium), followed for at least 12 weeks and compared with controls using a LABA in isolation or in combination with a corticosteroid. Results: A total of 2,622 studies were analyzed for possible inclusion on the basis of their title and abstract; 9 studies (17,120 participants) were included in the analysis. In comparison with LABAs, LAMAs led to a greater decrease in the exacerbation rate ratio (relative risk [RR] = 0.88; 95% CI: 0.84-0.93]; a lower proportion of patients who experienced at least one exacerbation (RR = 0.90; 95% CI: 0.87-0.94; p < 0.00001); a lower risk of exacerbation-related hospitalizations (RR = 0.78; 95% CI: 0.69-0.87; p < 0.0001); and a lower number of serious adverse events (RR = 0.81; 95% CI: 0.67-0.96; p = 0.0002). The overall quality of evidence was moderate for all outcomes. Conclusions: The major findings of this systematic review and meta-analysis were that LAMAs significantly reduced the exacerbation rate (exacerbation episodes/year), as well as the number of exacerbation episodes, of hospitalizations, and of serious adverse events.

RESUMO Objetivo: Determinar se long-acting muscarinic antagonists (LAMAs, antagonistas muscarínicos de longa duração) são superiores a long-acting β2 agonists (LABAs, β2-agonistas de longa duração) na prevenção de exacerbações da DPOC. Métodos: Revisão sistemática e meta-análise de ensaios clínicos controlados aleatórios com pacientes com DPOC estável, de moderada a grave, conforme os critérios da Global Initiative for Chronic Obstructive Lung Disease, tratados com LAMA (brometo de tiotrópio, aclidínio ou glicopirrônio), acompanhados durante pelo menos 12 semanas e comparados a controles que usaram LABA isoladamente ou com um corticosteroide. Resultados: Foram analisados 2.622 estudos para possível inclusão com base em seu título e resumo; 9 estudos (17.120 participantes) foram incluídos na análise. Em comparação com LABAs, LAMAs resultaram em maior diminuição da razão da taxa de exacerbações [risco relativo (RR) = 0,88; IC95%: 0,84-0,93]; menor proporção de pacientes que apresentaram pelo menos uma exacerbação (RR = 0,90; IC95%: 0,87-0,94; p < 0,00001); menor risco de hospitalizações em virtude de exacerbação da doença (RR = 0,78; IC95%: 0,69-0,87; p < 0,0001) e menor número de eventos adversos sérios (RR = 0,81; IC95%: 0,67-0,96; p = 0,0002). A qualidade geral das evidências foi moderada para todos os desfechos. Conclusões: O principal achado desta revisão sistemática e meta-análise foi que LAMAs reduziram significativamente a taxa de exacerbações (episódios de exacerbação/ano), os episódios de exacerbação, as hospitalizações e os eventos adversos sérios.

Short-term effects of fine particulate matter pollution on daily health events in Latin America: a systematic review and meta-analysis.

OBJECTIVES: Ambient air pollution is among the leading risks for health worldwide and by 2050 will largely overcome deaths due to unsafe sanitation and malaria, but local evidence from Latin America (LA) is scarce. We aimed to summarize the effect of short-term exposure to fine particulate air pollution (PM2.5) on morbidity and mortality in Latin America and evaluate evidence coverage and quality, using systematic review and meta-analysis. METHODS: The comprehensive search (six online databases and hand-searching) identified studies investigating the short-term associations between PM2.5 and daily health events in LA. Two reviewers independently accessed the internal validity of the studies and used random-effect models in the meta-analysis. RESULTS: We retrieved 1628 studies. Nine were elected for the qualitative analysis and seven for the quantitative analyses. Each 10 µg/m3 increments in daily PM2.5 concentrations was significantly associated with increased risk for respiratory and cardiovascular mortality in all-ages (polled RR = 1.02, 95% CI, 1.02-1.02 and RR = 1.01, 95% CI , 1.01-1.02, respectively). CONCLUSIONS: Short-term exposure to PM2.5 in LA is significantly associated with increased risk for respiratory and cardiovascular mortality. Evidence is concentrated in few cities and some presented high risk of bias.

Association between high consumption of phytochemical-rich foods and anthropometric measures: a systematic review.

Phytochemical-rich foods consumption may be a valid nutritional strategy to reduce the risk of weight gain and obesity. The phytochemical index (PI) is a simple and nonspecific method to evaluate the phytochemical intake, defined as the percentage of dietary calories derived from foods rich in phytochemicals. We aimed to conduct a systematic review to evaluate whether high consumption of phytochemical-rich foods evaluated by the PI is associated with lower values of anthropometric measurements. The available literature suggests that the PI seems to be inversely associated with body weight and waist circumference. Analyzing the longitudinal changes in anthropometric variables, individuals with high intake of phytochemicals gained less weight and fat mass when compared to those with lower PI. Our findings suggest that higher PI is associated with lower body mass index, waist circumference and adiposity. Whether the results are a reflex of a lower calorie intake or the anti-obesity properties of phytochemicals remains to be elucidated.

Echocardiography for prognostication during the resuscitation of intensive care unit patients with non-shockable rhythm cardiac arrest.

AIM: Transthoracic echocardiography (TTE) during cardiopulmonary arrest (CPA) has been studied in victims of cardiac arrests. Our objective was to evaluate the feasibility and usefulness of TTE in victims of cardiac arrest with non-shockable rhythms hospitalized in intensive care units (ICUs). METHODS: This prospective and observational cohort study evaluated ICU patients with CPA in asystole or pulseless electrical activity (PEA). Intensivists performed TTE during intervals of up to 10s as established in the treatment protocol. Myocardial contractility was defined as intrinsic movement of the myocardium coordinated with cardiac valve movement. PEA without contractility was classified as electromechanical dissociation (EMD), and with contractility as pseudo-EMD. The images, the rates of return of spontaneous circulation (ROSC) and the survival upon hospital discharge and after 180 days were evaluated. RESULTS: A total of 49 patients were included. Image quality was considered adequate in all cases and contributed to the diagnosis of CPA in 51.0% of the patients. Of the 49 patients included, 17 (34.7%) were in asystole and 32 (65.3%) in PEA, among which 5 (10.2%) were in EMD and 27 (55.1%) in pseudo-EMD. The rates of ROSC were 70.4% for those in pseudo-EMD, 20.0% for those in EMD, and 23.5% for those in asystole. Survival upon hospital discharge and after 180 days occurred only in patients in pseudo-EMD (22.2% and 14.8%, respectively). CONCLUSIONS: TTE conducted during cardiopulmonary resuscitation in ICU patients can be performed without interfering with care protocols and can contribute to the differential diagnosis of CPA and to the identification of a subgroup of patients with better prognosis.

Is there evidence for recommending specific intravenous immunoglobulin formulations? A systematic review of head-to-head randomized controlled trials.

Intravenous immunoglobulins (IVIG) have been used for several licensed and off-label indications. Each IVIG product is a unique formulation of IgG and excipients, making them distinct products. How these differences impact on individual IVIG product efficacy and safety are not well established but can be investigated by head-to-head randomized controlled trials (RCT). A systematic review of head-to-head RCT comparing different formulations of IVIG, regardless of the target condition and outcomes investigated. Two reviewers screened 4084 citations retrieved from MEDLINE, Embase, Cochrane and LILACS, and 23 citations were fully-text evaluated. Eight trials were included. The clinical conditions, outcomes and risk of bias were assessed. Of the eight trials included only two investigated products that are currently on the market. One evaluated two Grifols brands used in patients with primary immunodeficiency and another evaluated two Baxter brands used in patients with chronic inflammatory demyelinating polyradiculoneuropathy. There were no differences between the formulations for the outcomes evaluated. In the other trials, either the manufacturers were acquired by other companies or the formulation was withdrawn from the market. As consequence, evidence concerning these products could not be considered. The quality of the studies was low, showing high risk of bias. Direct evidence about the different IVIGs is scarce and, at present, there is no scientific evidence that can be applied for a specific brand or formulation. Further comparative effectiveness studies are highly desirable for a better understanding of the differences in safety and efficacy of IVIGs.

Effects of alveolar recruitment maneuvers on clinical outcomes in patients with acute respiratory distress syndrome: a systematic review and meta-analysis.

PURPOSE: To assess the effects of alveolar recruitment maneuvers (ARMs) on clinical outcomes in patients with acute respiratory distress syndrome (ARDS). METHODS: We conducted a search of the MEDLINE, EMBASE, LILACS, CINAHL, CENTRAL, Scopus, and Web of Science (from inception to July 2014) databases for all (i.e. no language restriction) randomized controlled trials (RCTs) evaluating the effects of ARMs versus no ARMs in adults with ARDS. Four teams of two reviewers independently assessed the eligibility of the studies identified during the search and appraised the risk of bias and extracted data from those which were assessed as meeting the inclusion criteria. Data were pooled using the random-effects model. Trial sequential analysis (TSA) was used to establish monitoring boundaries to limit global type I error due to repetitive testing for our primary outcome (in-hospital mortality). The GRADE system was used to rate the quality of evidence. RESULTS: Our database search identified ten RCTs (1,594 patients, 612 events) which satisfied the inclusion criteria. The meta-analysis assessing the effect of ARMs on in-hospital mortality showed a risk ratio (RR) of 0.84 [95 % confidence interval (CI) 0.74-0.95; I(2) = 0 %], although the quality of evidence was considered to be low due to the risk of bias in the included trials and the indirectness of the evidence--that is, ARMs were usually conducted together with other ventilatory interventions which may affect the outcome of interest. There were no differences in the rates of barotrauma (RR 1.11; 95 % CI 0.78-1.57; I(2) = 0 %) or need for rescue therapies (RR 0.76, 95 % CI 0.41-1.40; I(2) = 56 %). Most trials found no difference between groups in terms of duration of mechanical ventilation and length of stay in the intensive care unit and hospital. The TSA showed that the available evidence for the effect of ARMs on in-hospital mortality is precise in the case of a type I error of 5 %, but it is not precise with a type I error of 1 %. CONCLUSIONS: Although ARMs may decrease the mortality of patients with ARDS without increasing the risk for major adverse events, current evidence is not definitive. Large-scale ongoing trials addressing this question may provide data better applicable to clinical practice.