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PURPOSE: To quantitatively assess the benefit-risk ratio on the efficacy and safety of all phosphodiesterase type 5 inhibitors (PDE5i) in men with erectile dysfunction. METHODS: A systematic review with network meta-analysis, surface under the cumulative ranking analysis and stochastic multicriteria acceptability analyses were performed. Searches were conducted in Pubmed, Scopus, Web of Science without limits for time-frame or language. Randomized controlled trials evaluating the efficacy or safety of any PDE5i compared to a placebo or to other PDE5i in males with erectile disfunction were included. RESULTS: Overall, 184 articles representing 179 randomized controlled trials (50,620 patients) were included. All PDE5i were significantly more efficient than placebo. Sildenafil 25 mg was statistically superior to all interventions in enhancing IIEF (with a 98% probability of being the most effective treatment), followed by sildenafil 50 mg (80% of probability). Taladafil 10 mg and 20 mg also presented good profiles (73% and 76%, respectively). Avanafil and lodenafil were less effective interventions. Mirodenafil 150 mg was the treatment that caused more adverse events, especially flushing and headaches. Sildenafil 100 mg was more related to visual disorders, while vardenafil and udenafil were more prone to cause nasal congestion. CONCLUSION: Sildenafil at low doses and tadalafil should be the first therapeutic options. Avanafil, lodenafil and mirodenafil use are hardly justified given the lack of expressive efficacy or high rates of adverse events.
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Técnicas de Apoio para a Decisão , Disfunção Erétil/tratamento farmacológico , Inibidores da Fosfodiesterase 5/administração & dosagem , Administração Oral , Humanos , Masculino , Metanálise em Rede , Inibidores da Fosfodiesterase 5/efeitos adversos , Resultado do TratamentoRESUMO
Treatment options for myelodysplastic syndromes (MDS) vary widely, depending on the natural disease course and patient-related factors. Comparison of treatment effectiveness is challenging as different endpoints have been included in clinical trials and outcome reporting. Our goal was to develop the first MDS core outcome set (MDS-COS) defining a minimum set of outcomes that should be reported in future clinical studies. We performed a comprehensive systematic literature review among MDS studies to extract patient- and/or clinically relevant outcomes. Clinical experts from the European LeukemiaNet MDS (EUMDS) identified 26 potential MDS core outcomes and participated in a three-round Delphi survey. After the first survey (56 experts), 15 outcomes met the inclusion criteria and one additional outcome was included. The second round (38 experts) resulted in six included outcomes. In the third round, a final check on plausibility and practicality of the six included outcomes and their definitions was performed. The final MDS-COS includes: health-related quality of life, treatment-related mortality, overall survival, performance status, safety, and haematological improvement. This newly developed MDS-COS represents the first minimum set of outcomes aiming to enhance comparability across future MDS studies and facilitate a better understanding of treatment effectiveness.
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Síndromes Mielodisplásicas/epidemiologia , Terapia Combinada , Técnica Delphi , Gerenciamento Clínico , Humanos , Síndromes Mielodisplásicas/terapia , Avaliação de Resultados em Cuidados de Saúde , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Sistema de Registros , Inquéritos e QuestionáriosRESUMO
PURPOSE: Although randomized controlled trials (RCTs) are the gold standard for the assessment of clinical outcomes, long-term extension trials (LTEs) and observational cohorts may help generate evidence. Our goal was to compare the discontinuation rates of abatacept, rituximab, and tocilizumab in rheumatoid arthritis (RA) reported in different study designs. METHODS: A systematic review was conducted with searches in PubMed, Scopus, and the Cochrane Library, plus a manual search, for RCTs, LTEs, and observational cohorts reporting discontinuation rates by any of three causes (all-cause, inefficacy, adverse events). Meta-analyses with sensitivity analyses and meta-regressions were conducted. RESULTS: Of the 111 studies included, 74 were RCTs (n = 55) or LTEs (n = 17) reporting data on abatacept (n = 33), rituximab (n = 10), and tocilizumab (n = 31) and 37 were observational cohort studies (abatacept = 11, rituximab = 8, tocilizumab = 18). The follow-up duration did not differ among the study designs. Discontinuation rates were similar among the drugs but varied among the study designs. Discontinuation rates were significantly higher in cohort studies than those in interventional studies for the three drugs. Sensitivity analyses could not identify patient characteristics associated with these differences. Meta-regression analyses demonstrated no correlation between study follow-up duration and discontinuation rates. CONCLUSIONS: The discontinuation rates reported for non-anti-TNF drugs varied relative to the study design in which they were investigated. Regulatory agencies, price-setting entities, and evidence-gathering researchers should consider the effect of the real-life environment in their decisions and conclusions.
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Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Projetos de Pesquisa , Abatacepte/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Rituximab/administração & dosagemRESUMO
PURPOSE: Acromegaly is a rare disease that results in the enlargement of body extremities and in organomegaly. Treatments include surgery, drugs, and radiotherapy, which are all onerous. Therefore, well-conducted cost-analyses are crucial in the decision-making process. METHODS: A systematic review of cost-effectiveness studies on acromegaly therapies was performed following PRISMA and Cochrane recommendations. The search for records was conducted in PubMed, Scopus, and Web of Science (May 2018). The quality of the included studies was assessed using the Joana Briggs Institute Tool. RESULTS: From initial 547 records, 16 studies were included in the review. The studies could present more than one economic evaluation, and encompassed cost-effectiveness (n = 13), cost-utility (n = 5), and cost-consequence (n = 1) analyses. All studies were model-based and evaluated only direct medical costs. Eleven records did not mention discounting and only 10 performed sensitivity analyses. The characteristic of the studies, the cost-effectiveness results and the studies' conclusions are described and commented upon. The main limitation of the studies was discussed and aspects to improve in future studies were pointed out. CONCLUSIONS: Cost-effectiveness studies on acromegaly have been performed in several scenarios, evaluating different phases of treatment. However, the studies present limitations and, overall, were considered of moderate quality. Further economic models should be developed following health economics guidelines recommendations, and must improve transparency.
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Acromegalia/tratamento farmacológico , Acromegalia/economia , Análise Custo-Benefício , Hormônio do Crescimento Humano/análogos & derivados , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Octreotida/uso terapêutico , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Somatostatina/uso terapêuticoRESUMO
The aim of this study is to gather evidence of head-to-head double-blind randomized-controlled trials on the efficacy and safety of available treatments for attention deficit hyperactivity disorder (ADHD) in children and adolescents. A systematic review was conducted by two independent reviewers in ten electronic databases (PROSPERO register CRD42016043239). Methodological quality of included studies was evaluated according to the Jadad scale. Network meta-analyses were performed including double-blinded head-to-head trials comparing active allopathic drugs in patients (0-18 years old) diagnosed with ADHD. The results of efficacy and safety of atomoxetine (ATX), bupropion, buspirone (BSP), dexamphetamine, edivoxetine (EDX), guanfacine (GXR), lisdexamfetamine (LDX), methylphenidate (MPH), mixed amphetamine salts, modafinil, pindolol (PDL), reboxetine (RBX), selegiline, and venlafaxine were analyzed using ADDIS software v.1.16.5. Forty-eight trials were identified (n = 4169 participants), of which 12 were used for efficacy analysis and 33 for safety analysis. On the CGI-I scale, the analysis revealed that MPH was more effective than ATX and GXR. For the safety outcomes, according to drug ranks, LDX was more likely to cause sleep disorders (39%) as well as loss of appetite (65%) and behavior problems such as irritability (60%). BSP (71%) and EDX (44%) caused less appetite decrease. For behavioral effects, PDL was considered safest (50%). For any adverse events, RBX (89%) was the safest alternative. The lack of head-to-head trials properly reporting outcomes of interest limited some comparisons. Network meta-analysis offered a broader overview on the available treatments for ADHD, especially for safety issues, and contributes towards evidence gathering and clinical practice decisions. A core outcome set for ADHD should be designed to guide the conduction and report of clinical trials.
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Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Criança , Feminino , Humanos , Masculino , Resultado do TratamentoRESUMO
BACKGROUND AND AIM: Ledipasvir with sofosbuvir (LED/SOF) for the treatment of patients infected with genotype 1 hepatitis C virus can be used with or without ribavirin (RBV). RBV is well known to promote significant adverse events (AE). The aim of this study was to compare the efficacy and safety of treatment with LED/SOF, with or without RBV, in patients infected with hepatitis C virus genotype 1. METHODS: We performed a systematic review followed by a pairwise meta-analysis including randomized controlled trials that reported efficacy (rapid virological response, sustained virological response at 4 and 12 weeks post-treatment (SVR4 and 12), and viral relapse) and safety outcomes (any AE, serious AE, discontinuation owing to AE, anemia, and rash). It was performed a subgroup analysis evaluating the SVR12 including only cirrhotic patients. Results were reported as risk ratios (RR) and with 95% confidence intervals (95% CI). RESULTS: Seven randomized controlled trials were analyzed. LED/SOF with RBV showed a worse safety profile when compared with LED/SOF without RBV for the following outcomes: any AE (RR 0.56 [95% CI 0.46-0.69]), anemia (RR 0.08 [95% CI 0.04-0.17]), and rash (RR 0.35 [95% CI 0.19-0.65]). No significant differences were observed regarding serious AE, rapid virological response, SVR4, SVR12, or viral relapse. The subgroup analysis did not show significant differences between either treatment groups. CONCLUSION: Administration of LED/SOF + RBV to treatment-naïve patients with or without cirrhosis, and non-cirrhotic treatment-experienced patients, did not promote significant additional benefits. Furthermore, it is still unclear whether cirrhotic treatment-experienced patients could benefit from combined therapy.
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Antivirais/administração & dosagem , Benzimidazóis/administração & dosagem , Fluorenos/administração & dosagem , Genótipo , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Ribavirina/administração & dosagem , Sofosbuvir/administração & dosagem , Antivirais/efeitos adversos , Benzimidazóis/efeitos adversos , Bases de Dados Bibliográficas , Quimioterapia Combinada , Fluorenos/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Ribavirina/efeitos adversos , Sofosbuvir/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: This study aimed to compare the efficacy among direct-acting antiviral agents (first and second-generation direct-acting antiviral agents (DAAs)) with placebo and with standard dual therapy (pegylated interferon + ribavirin (Peg-IFN + RBV)) in terms of rapid virologic response (RVR) and sustained virologic response (SVR) in chronic hepatitis C genotype 1 treatment. METHODS: We performed a systematic review of randomized controlled trials (RCTs) in MEDLINE, International Pharmaceutical Abstracts, Cochrane Library, SCIELO, and Scopus and conducted a network meta-analysis to compare the efficacy of boceprevir (BOC), daclatasvir (DCV), grazoprevir, simeprevir (SMV) and telaprevir (TVR), in treatment-naive and treatment-experienced patients. RESULTS: Sixteen studies encompassing 7171 patients were analysed. Associations between DAAs therapies (IFN-free regimens) could not be addressed since no common comparator was found in the RCTs among these associations and the other agents included in the present analysis. All agents were more efficacious than placebo or Peg-IFN + RBV in terms of RVR, while only BOC and SMV showed statistically significant superiority for the SVR outcome when compared to placebo or standard dual therapy. No significant differences between the DAAs were observed. The analysis prioritized treatment with DCV for both efficacy outcomes. Node-splitting analysis showed that our networks are robust (p > 0.05). CONCLUSIONS: The superiority of DAAs over placebo or standard dual therapy with Peg-IFN + RBV was confirmed, indicating the greater efficacy of DCV. This study is the first network meta-analysis that included RVR as an outcome in the evaluation of these agents via indirect comparison. Further investigation should be carried out addressing safety and tolerability outcomes.
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Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Genótipo , Humanos , Interferons/uso terapêutico , Metanálise em Rede , Polietilenoglicóis/uso terapêutico , Ribavirina/uso terapêutico , Resposta Viral SustentadaRESUMO
Invasive fungal infections, an important cause of mortality, are primarily treated using amphotericin B, which is available in different formulations, both conventional and lipid-based (liposomal, lipid complex, colloidal dispersion and Intralipid® infusion). The aim of our study was to determine the efficacy and safety of conventional amphotericin B vs its lipid-based formulations. A systematic review followed by pairwise meta-analysis was performed, including randomised controlled trials (RCTs) that evaluated the use of lipid-based amphotericin B in patients with any degree of immunosuppression and susceptibility to invasive fungal infection. An electronic search was conducted using PubMed, Scopus, Web of Science and Scielo databases. Extracted outcomes were related to efficacy (cure) and safety (incidence of adverse events). Results were evaluated and meta-analyses were performed. Twenty-three RCTs were identified (n=2677 participants) for meta-analysis. No significant differences between conventional amphotericin B and any of the five formulations evaluated were observed, with regard to the efficacy analysis. With respect to the adverse events of nephrotoxicity, fever, chills and vomiting, all lipid formulations presented better profiles than the conventional formulation. The present systematic review and meta-analysis showed that conventional amphotericin B presents the same efficacy profile as lipid-based formulations, although the latter were associated with a safer profile.
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Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Infecções Fúngicas Invasivas/tratamento farmacológico , Anfotericina B/efeitos adversos , Anfotericina B/uso terapêutico , Antifúngicos/efeitos adversos , Antifúngicos/uso terapêutico , Ensaios Clínicos como Assunto , Coloides , Composição de Medicamentos , Emulsões , Febre , Humanos , Infecções Fúngicas Invasivas/microbiologia , Infecções Fúngicas Invasivas/mortalidade , Lipídeos , Fosfolipídeos , Óleo de SojaRESUMO
OBJECTIVES: This study aimed to perform a cost-effectiveness analysis (CEA) of the molecular diagnostic method (MM) associated with conventional diagnostic method (CM) compared with the CM alone, for the detection of resistant profile in bacteremia, from the perspective of the Brazilian Public Health System, in intensive care units setting. METHODS: The clinical parameters regarding methicillin-resistant Staphylococcus aureus (MRSA), carbapenem-resistant Gram-negative bacteria (CRGNB), and vancomycin-resistant Enterococcus spp. (VRE) infections were collected from searches on PubMed, Scopus, and SciELO, using specific keywords. Data on direct medical costs to treat these infections were collected according to Brazilian Public Health System perspective from Brazilian databases, in tables of 2018 to 2019. CEA was performed after building a dynamic model, which was calibrated and validated according to international recommendations. The incremental cost-effectiveness ratio of the MM + CM compared with the CM was calculated using the outcomes "avoided death" and "avoided resistant infections." One-way sensitivity analyses were performed. RESULTS: This CEA demonstrated that the MM + CM was dominant in all scenarios. Estimates showed that for MRSA, CRGNB, and VRE infections, every avoided death would lead to savings of Brazilian real (R$) 4.9 million ($937 301), R$2.2 million ($419 899), and R$1.3 million ($248 919), respectively. The same infections assessed by avoided resistant infections savings were projected to be R$24 964 ($4686), R$40 260 ($7558), and R$23 867 ($4480). CONCLUSIONS: MM leads to cost reduction and increased benefits, optimizing the use of financial resources on the health system in the intensive care unit setting, in bacteremia caused by MRSA, CRGNB, and VRE.
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Infecções por Bactérias Gram-Positivas , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Antibacterianos/uso terapêutico , Análise Custo-Benefício , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos , Infecções Estafilocócicas/diagnóstico , Infecções Estafilocócicas/tratamento farmacológicoRESUMO
The safety of using different antiretroviral therapies (ART) in pediatric HIV/AIDS patients is not well-established. Therefore, this study aimed to assess the safety of ART in children. A systematic review of randomized clinical trials (RCTs) was conducted to assess the safety of ART used by pediatric patients living with HIV/AIDS. The electronic search was conducted in PubMed and Scopus, in addition to a manual search. Studies were included if they assessed the safety of ART compared to placebo or another ART. Direct and indirect meta-analyses were conducted regarding safety outcomes. The systematic review included 21 RCTs. The studies included more than 5500 participants, and age ranged from 3 months to 18 years. The drugs evaluated were nucleoside reverse transcriptase inhibitors (NRTI); non-NRTI; and protease inhibitors. The predominant route of infection was vertical. Direct meta-analyses were performed for the outcomes sleep disorders, hepatobiliary disorders, respiratory disorders, hypertransaminasemia, neutropenia, hospitalization, and death. For these outcomes, no statistically significant differences were found. Indirect meta-analyses were performed for the outcomes anemia, gastrointestinal disorders, liver disorders, severe adverse events (AE), AE that led to changes in treatment, fever, and skin manifestations. However, no statistically significant differences were found for these outcomes. In this study, non-significant differences were detected in the safety of different ART used in pediatric individuals. The choice of appropriate therapy should be based on its efficacy and the individual characteristics of each patient.
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Síndrome da Imunodeficiência Adquirida , Fármacos Anti-HIV , Infecções por HIV , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Criança , Quimioterapia Combinada , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Inibidores da Transcriptase ReversaRESUMO
Introduction: Considering the need for effective postmarketing surveillance of disease-modifying therapies (DMTs) in multiple sclerosis (MS), we analyzed the potential of the spontaneous reports for safety signal detection, verifying the completeness of the reports in the FDA Adverse Event Reporting System (FAERS).Methods: All reports with DMTs for MS considered the primary suspect cause of ADRs and registered between January 2004 and June 2019 were selected. The vigiGrade completeness score was applied and reports with a score greater than 0.80 were considered well documented. Descriptive statistical analysis and comparisons of well-documented reports by DMTs were performed.Results: A total of 297,926 reports were analyzed. The lowest completeness rates were observed for type of report (13.5%), dose (62.7%), and time from treatment start to the ADR (79.0%). Overall, 80.8% of reports were classified as well documented and those related to natalizumab had the highest proportion (92.4%, p < 0.001), while the lowest was observed for reports sent in 2017 (53.1%, p < 0.001) and for teriflunomide (48.5%, p < 0.001).Conclusions: The high proportion of well-documented reports for DMTs indicates that they can be a valuable source for safety signal detection. A more careful analysis should be performed for data from the groups identified with low completeness to avoid the disclosure of spurious results.
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Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Esclerose Múltipla/tratamento farmacológico , Vigilância de Produtos Comercializados/estatística & dados numéricos , Sistemas de Notificação de Reações Adversas a Medicamentos/normas , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Farmacovigilância , Vigilância de Produtos Comercializados/normas , Estados Unidos , United States Food and Drug AdministrationRESUMO
The incidence of pediatric adrenocortical tumors (ACT) is high in southern Brazil due to the founder TP53 R337H variant. Neonatal screening/surveillance (NSS) for this variant resulted in early ACT detection and improved outcomes. The medical records of children with ACT who did not participate in newborn screening (non-NSS) were reviewed (2012-2018). We compared known prognostic factors between the NSS and non-NSS cohorts and estimated surveillance and treatment costs. Of the 16 non-NSS children with ACT carrying the R337H variant, the disease stages I, II, III, and IV were observed in five, five, one, and five children, respectively. The tumor weight ranged from 22 to 608 g. The 11 NSS children with ACT all had disease stage I and were alive. The median tumor weight, age of diagnosis, and interval between symptoms and diagnosis were 21 g, 1.9 years, and two weeks, respectively, for the NSS cohort and 210 g, 5.2 years, and 15 weeks, respectively, for the non-NSS cohort. The estimated surveillance/screening cost per year of life saved is US$623/patient. NSS is critical for improving the outcome of pediatric ACT in this region. Hence, we strongly advocate for the inclusion of R337H in the state-mandated universal screening and surveillance.
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OBJECTIVES: Current evidence on fecal microbiota transplantation for inflammatory bowel disease is inconclusive. We conducted a systematic review to gather evidence on the efficacy and safety of fecal microbiota transplantation for inflammatory bowel disease. METHODS: Systematic searches were conducted in PubMed, Scopus, and Web of Science. Clinical remission was considered as the primary endpoint. Pairwise meta-analyses were performed for the randomized controlled studies (Mantel Haenszel, random effects model). Proportion meta-analyses, accounting for weighted pooled rates reported in the interventional studies, were conducted using the mixed effects model. Subgroup analyses considering the type of stool, donor type, and disease subtype were also performed. Cumulative meta-analyses to assess further needs of evidence were conducted. RESULTS: Sixty studies were included, from which 36 could be synthesized in the quantitative analyses. Pairwise meta-analyses of six controlled trials showed significant differences in favor of fecal microbiota transplantation compared with placebo (clinical remission: RR 1.70 [95% CI 1.12, 2.56]; clinical response: RR 1.68 [95% CI 1.04, 2.72]). An overall clinical remission of 37%, overall clinical response of 54%, and a prevalence of 29% of adverse events were found for the interventional studies. Frozen fecal material and universal donors were related to better efficacy outcomes. In addition, Crohn's disease patients seemed to benefit more from the procedure. CONCLUSIONS: The comparative analyses demonstrated that frozen fecal material from universal donors may be related to a higher rate of clinical remission, especially for Crohn's disease.
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Transplante de Microbiota Fecal/métodos , Doenças Inflamatórias Intestinais/terapia , Transplante de Microbiota Fecal/efeitos adversos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Resultado do TratamentoRESUMO
BACKGROUND: The conduction and report of network meta-analysis (NMA), including the presentation of the network-plot, should be transparent. We aimed to propose metrics adapted from graph theory and social network-analysis literature to numerically describe NMA geometry. METHODS: A previous systematic review of NMAs of pharmacological interventions was performed. Data on the graph's presentation were collected. Network-plots were reproduced using Gephi 0.9.1. Eleven geometric metrics were tested. The Spearman test for non-parametric correlation analyses and the Bland-Altman and Lin's Concordance tests were performed (IBM SPSS Statistics 24.0). RESULTS: From the 477 identified NMAs only 167 graphs could be reproduced because they provided enough information on the plot characteristics. The median nodes and edges were 8 (IQR 6-11) and 10 (IQR 6-16), respectively, with 22 included studies (IQR 13-35). Metrics such as density (median 0.39, ranged 0.07-1.00), median thickness (2.0, IQR 1.0-3.0), percentages of common comparators (median 68%), and strong edges (median 53%) were found to contribute to the description of NMA geometry. Mean thickness, average weighted degree and average path length produced similar results than other metrics, but they can lead to misleading conclusions. CONCLUSIONS: We suggest the incorporation of seven simple metrics to report NMA geometry. Editors and peer-reviews should ensure that guidelines for NMA report are strictly followed before publication.
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Metanálise em Rede , Bibliometria , Mineração de Dados , Bases de Dados Bibliográficas , Humanos , EditoraçãoRESUMO
BACKGROUND: We aimed to determine the methodological quality of network meta-analyses (NMAs) and their compliance with reporting guidelines. METHODS: A systematic review of NMAs comparing any pharmacological interventions was performed (searches in Medline and Scopus). The characteristics of NMAs were collected by two independent reviewers. We applied R-AMSTAR to all NMAs, generating a methodological quality score that could range from 11 to 44 points. PRISMA and PRISMA-NMA reporting checklists were converted into quantitative scores (maximum values of 27 and 32 points). To normalize the values between these two checklists, a third score (PRISMA-SCORE) of 0-1 was created. The correlation of the scores with NMA publication year, journal impact factor and most productive countries were calculated using non-parametric tests. RESULTS: We identified 477 NMAs. Only 36.1% of studies reported having followed PRISMA statements. The medians of R-AMSTAR, PRISMA and PRISMA-NMA scores were 28 (IQR 25-31), 21 (IQR 19-23) and 23 (IQR 19-26), respectively. Several problems were noted in NMAs (e.g. lack of study protocol, issues in literature searches, lack of raw data). NMAs from the most productive countries (USA and China) have similar methodological quality. Correlation analyses between R-AMSTAR and normalized PRISMA-SCORE revealed a strong positive correlation (Spearman's ρ = 0.776; P <0.001). A weak but positive correlation was found for PRISMA-SCORE and journal impact factor (0.193; P <0.001). CONCLUSIONS: The important growth of NMA publication rate during the past 5 years is not associated with better methodological and reporting quality. Editors, peer reviewers, researchers and funding agencies should ensure that methodological and reporting standards are met before publication.
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Tratamento Farmacológico/métodos , Metanálise em Rede , Algoritmos , Teorema de Bayes , Lista de Checagem , Tomada de Decisões , Humanos , Internet , MEDLINE , Preparações Farmacêuticas , Projetos de Pesquisa , SoftwareRESUMO
OBJECTIVES: Because of the lack of evidence regarding long-term effectiveness and cost-effectiveness of first-generation direct-acting antivirals for chronic hepatitis C (CHC) treatment in Brazil, we performed a cost-utility analysis comparing standard dual therapy (peginterferon plus ribavirin [pegIFN/RBV]), boceprevir, and telaprevir for CHC patients. METHODS: We developed a state-transition Markov model simulating the progression of CHC. Long-term outcomes included remaining life expectancy in life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Short-term outcomes included sustained virological response rates (SVR). Direct medical costs were obtained from Brazilian databases. A lifelong time horizon was considered and a 5% annual discount rate was applied for costs and clinical outcomes. A willingness-to-pay threshold of approximately $20 000 per QALY was used. We performed multiple sensitivity analyses. RESULTS: For short- and long-term scenarios, therapy with boceprevir was dominated by telaprevir, which was more effective than standard dual therapy (75.0% vs 40.4% SVR rate, 13.47 vs 12.59 LYs, and 9.74 vs 8.49 QALYs, respectively) and was also more expensive ($15 742 vs $5413). The corresponding ICERs were $29 854/SVR, $11 803/LY, and $8277/QALY. Based on our model, triple therapy with telaprevir was the most cost-effective treatment for the Brazilian health system. Despite a lack of data regarding the Brazilian population, we incorporated as many applicable parameters as possible. CONCLUSIONS: Telaprevir is more effective and cost-effective than boceprevir. Our model may be applied for other settings with a few adjustments in the input parameters.
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Antivirais/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Oligopeptídeos/uso terapêutico , Prolina/análogos & derivados , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Brasil , Análise Custo-Benefício , Custos de Medicamentos , Quimioterapia Combinada , Feminino , Custos de Cuidados de Saúde/estatística & dados numéricos , Hepatite C Crônica/economia , Humanos , Interferon-alfa/administração & dosagem , Interferon-alfa/economia , Interferon-alfa/uso terapêutico , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Oligopeptídeos/economia , Prolina/administração & dosagem , Prolina/economia , Prolina/uso terapêutico , Prática de Saúde Pública/economia , Prática de Saúde Pública/estatística & dados numéricos , Anos de Vida Ajustados por Qualidade de Vida , Ribavirina/administração & dosagem , Ribavirina/economia , Ribavirina/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: The molecular and pharmacological complexity of biologic disease-modifying antirheumatic drugs used for the management of rheumatoid arthritis (RA) favors the occurrence of adverse drug reactions (ADRs), which should be constantly monitored in post-marketing safety studies. OBJECTIVE: The aim of this study was to identify signals of disproportionate reporting (SDR) of clinical relevance related to the use of biologic drugs approved for RA and other autoimmune diseases. METHODS: All suspected ADRs registered in the FDA Adverse Event Reporting System between January 2003 and June 2016 were collected. The reporting odds ratio was used as a measure of disproportionality to identify possible SDRs related to biologics. Those involving important medical events and designated medical events (DME) were prioritized. RESULTS: In total, 2602 SDRs were prioritized. The most commonly reported were 'Infections and infestations' (32.2%) and 'Neoplasms benign, malignant, and unspecified' (20.4%), and were mainly related to use of infliximab (25.3%, p < 0.001, and 28.8%, p = 0.002, respectively). Sixty-three signals involving DMEs were identified, most of which were related to rituximab (n = 27), and were mainly due to 'blood disorders'. Amongst the DMEs detected for more than one biologic, 'intestinal perforation' and 'pulmonary fibrosis' were related to most of them. CONCLUSIONS: The results of this study highlight possible safety issues associated with biologics, whose relationship should be more thoroughly investigated. Our results contribute to future research on the identification of clinically relevant risks associated with these drugs, and may help contribute to their rational and safe use.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Antirreumáticos/efeitos adversos , Produtos Biológicos/efeitos adversos , Bases de Dados Factuais/estatística & dados numéricos , United States Food and Drug Administration/estatística & dados numéricos , Humanos , Estados UnidosRESUMO
BACKGROUND: Network meta-analysis (NMA) is a new tool developed to overcome some limitations of pairwise meta-analyses. NMAs provide evidence on more than two comparators simultaneously. This study aimed to map the characteristics of the published NMAs on drug therapy comparisons. METHODS: A systematic review of NMAs comparing pharmacological interventions was performed. Searches in Medline (PubMed) and Scopus along with manual searches were conducted. The main characteristics of NMAs were systematically collected: publication metadata, criteria for drug inclusion, statistical methods used, and elements reported. A methodological quality score with 25 key elements was created and applied to the included NMAs. To identify potential trends, the median of the publication year distribution was used as a cut-off. RESULTS: The study identified 365 NMAs published from 2003 to 2016 in more than 30 countries. Randomised controlled trials were the primary source of data, with only 5% including observational studies, and 230 NMAs used a placebo as a comparator. Less than 15% of NMAs were registered in PROSPERO or a similar system. One third of studies followed PRISMA and less than 9% Cochrane recommendations. Around 30% presented full-search strategies of the systematic review, and 146 NMAs stated the selection criteria for drug inclusion. Over 75% of NMAs presented network plots, but only half described their geometry. Statistical parameters (model fit, inconsistency, convergence) were properly reported by one third of NMAs. Although 216 studies exhibited supplemental material, no data set of primary studies was available. The methodological quality score (mean 13·9; SD 3·8) presented a slightly positive trend over the years. CONCLUSION: The map of the published NMAs emphasises the potential of this tool to gather evidence in healthcare, but it also identified some weaknesses, especially in the report, which limits its transparency and reproducibility.
Assuntos
Tratamento Farmacológico/métodos , Metanálise em Rede , Algoritmos , Teorema de Bayes , Tomada de Decisões , Humanos , Internet , MEDLINE , Metanálise como Assunto , Preparações Farmacêuticas , Reprodutibilidade dos Testes , Projetos de Pesquisa , SoftwareRESUMO
BACKGROUND: Vitamins are essential micronutrients with antioxidant potential that may provide a complementary treatment for patients with chronic diseases. Our aim was to assess the effect of vitamin supplementation on the antioxidant status and glycemic index of type 2 diabetes mellitus patients. METHODS: We performed a systematic review with meta-analyses. Electronic searches were conducted in PubMed, Scopus, and Web of Science (December 2017). Randomized controlled trials evaluating the effect of any vitamin or vitamin complex supplementation on antioxidant status as primary outcome were included. The outcomes considered were: reduction of malondialdehyde (MDA); augmentation of glutathione peroxidase (GPx); changes in total antioxidant capacity (TAC), enhance in superoxide dismutase enzyme-SOD, and thiobarbituric acid reactive substances (TBARS). Outcomes of glycemic control were also evaluated. Pairwise meta-analyses were performed using software Review Manager 5.3. RESULTS: Thirty trials fulfilled the inclusion criteria, but only 12 could be included in the meta-analyses of antioxidant outcomes. The most commonly studied vitamins were B, C, D and E. Vitamin E was related to significant reduction of blood glucose as well as glycated hemoglobin compared to placebo, while both vitamins C and E were mainly associated with reducing MDA and TBARS and elevating GPx, SOD and TAC, compared to placebo. However, outcome reports in this field are still inconsistent (e.g. because of a lack of standard measures). CONCLUSIONS: Supplementation of vitamin E may be a valuable strategy for controlling diabetes complications and enhancing antioxidant capacity. The effects of other micronutrients should be further investigated in larger and well-designed trials to properly place these complementary therapies in clinical practice.
RESUMO
BACKGROUND: A broad range of disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) is available. However, the efficacy and safety of traditional DMTs compared with the recently developed DMTs remain unclear. OBJECTIVE: Therefore, we have synthesised available evidence of clinical outcomes for DMTs in adults with RRMS. METHODS: PubMed, Scopus and a manual search were performed. Bayesian network meta-analyses of randomised clinical trials assessing DMTs as monotherapies were conducted. SUCRA and GRADE were used to rank therapies and to assess quality of general evidence, respectively. RESULTS: Thirty-three studies were included in the meta-analyses. The most effective therapies for the outcome of annualised relapse rate were alemtuzumab (96% probability), natalizumab (96%) and ocrelizumab (85%), compared with all other therapies (hazard ratio versus placebo, 0.31, 0.31 and 0.37, respectively; p < 0.05 for all comparisons) (high-quality evidence). However, no significant differences among these three therapies were found. Discontinuation due to adverse events revealed similarity across all therapies, except for alemtuzumab, which showed less discontinuation when compared with interferon-1a intramuscular (relative risk 0.37; p < 0.05). CONCLUSION: High-quality evidence shows that alemtuzumab, natalizumab and ocrelizumab present the highest efficacy among DMTs, and other meta-analyses are required regarding adverse events frequency, to better understand the safety of therapies. Based on efficacy profile, guidelines should consider a three-category classification (i.e. high, intermediate and low efficacy).