Use of re-randomized data in meta-analysis

BACKGROUND: Outcomes collected in randomized clinical trials are observations of random variables that should be independent and identically distributed. However, in some trials, the patients are randomized more than once thus violating both of these assumptions. The probability of an event is not always the same when a patient is re-randomized; there is probably a non-zero covariance coming from observations on the same patient. This is of particular importance to the meta-analysts. METHODS: We developed a method to estimate the relative error in the risk differences with and without re-randomization of the patients. The relative error can be estimated by an expression depending on the percentage of the patients who were re-randomized, multipliers (how many times more likely it is to repeat an event) for the probability of reoccurrences, and the ratio of the total events reported and the initial number of patients entering the trial. RESULTS: We illustrate our methods using two randomized trials testing growth factors in febrile neutropenia. We showed that under some circumstances the relative error of taking into account re-randomized patients was sufficiently small to allow using the results in the meta-analysis. Our findings indicate that if the study in question is of similar size to other studies included in the meta-analysis, the error introduced by re-randomization will only minimally affect meta-analytic summary point estimate. We also show that in our model the risk ratio remains constant during the re-randomization, and therefore, if a meta-analyst is concerned about the effect of re-randomization on the meta-analysis, one way to sidestep the issue and still obtain reliable results is to use risk ratio as the measure of interest. CONCLUSION: Our method should be helpful in the understanding of the results of clinical trials and particularly helpful to the meta-analysts to assess if re-randomized patient data can be used in their analyses

Quality and methods of developing practice guidelines

BACKGROUND: It is not known whether there are differences in the quality and recommendations between evidence-based (EB) and consensus-based (CB) guidelines. We used breast cancer guidelines as a case study to assess for these differences. METHODS: Five different instruments to evaluate the quality of guidelines were identified by a literature search. We also searched MEDLINE and the Internet to locate 8 breast cancer guidelines. These guidelines were classified in three categories: evidence based, consensus based and consensus based with no explicit consideration of evidence (CB-EB). Each guideline was evaluated by three of the authors using each of the instruments. For each guideline we assessed the agreement among 14 decision points which were selected from the NCCN (National Cancer Comprehensive Network) guidelines algorithm. For each decision point we recorded the level of the quality of the information used to support it. A regression analysis was performed to assess if the percentage of high quality evidence used in the guidelines development was related to the overall quality of the guidelines. RESULTS: Three guidelines were classified as EB, three as CB-EB and two as CB. The EB guidelines scored better than CB, with the CB-EB scoring in the middle among all instruments for guidelines quality assessment. No major disagreement in recommendations was detected among the guidelines regardless of the method used for development, but the EB guidelines had a better agreement with the benchmark guideline for any decision point. When the source of evidence used to support decision were of high quality, we found a higher level of full agreement among the guidelines' recommendations. Up to 94% of variation in the quality score among guidelines could be explained by the quality of evidence used for guidelines development. CONCLUSION: EB guidelines have a better quality than CB guidelines and CB-EB guidelines. Explicit use of high quality evidence can lead to a better agreement among recommendations. However, no major disagreement among guidelines was noted regardless of the method for their development

Author Correction: Characterization of rifampicin-resistant Mycobacterium tuberculosis in Khyber Pakhtunkhwa, Pakistan.

The original version of this Article contained an error in the spelling of the author Otavio Cabral-Marques which was incorrectly given as Otavio Marques Cabral. The original Article has been corrected

Erythropoietin, uncertainty principle and cancer related anaemia

BACKGROUND: This study was designed to evaluate if erythropoietin (EPO) is effective in the treatment of cancer related anemia, and if its effect remains unchanged when data are analyzed according to various clinical and methodological characteristics of the studies. We also wanted to demonstrate that cumulative meta-analysis (CMA) can be used to resolve uncertainty regarding clinical questions. METHODS: Systematic Review (SR) of the published literature on the role of EPO in cancer-related anemia. A cumulative meta-analysis (CMA) using a conservative approach was performed to determine the point in time when uncertainty about the effect of EPO on transfusion-related outcomes could be considered resolved. Participants: Patients included in randomized studies that compared EPO versus no therapy or placebo. Main outcome measures: Number of patients requiring transfusions. RESULTS: Nineteen trials were included. The pooled results indicated a significant effect of EPO in reducing the number of patients requiring transfusions [odds ratio (OR) = 0.41; 95%CI: 0.33 to 0.5; p < 0.00001;relative risk (RR) = 0.61; 95% CI: 0.54 to 0.68]. The results remain unchanged after the sensitivity analyses were performed according to the various clinical and methodological characteristics of the studies. The heterogeneity was less pronounced when OR was used instead of RR as the measure of the summary point estimate. Analysis according to OR was not heterogeneous, but the pooled RR was highly heterogeneous. A stepwise metaregression analysis did point to the possibility that treatment effect could have been exaggerated by inadequacy in allocation concealment and that larger treatment effects are seen at hb level > 11.5 g/dl. We identified 1995 as the point in time when a statistically significant effect of EPO was demonstrated and after which we considered that uncertainty about EPO efficacy was resolved. CONCLUSION: EPO is effective in the treatment of anemia in cancer patients. This could have already been known in 1995 if a CMA had been performed at that time

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Fatores estimuladores de colonias para o tratamento da neurotropenia febril pos-quimioterapia : revisão sistematica da literatura e meta-analise

Orientador: Paulo Eduardo PizãoTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias MedicasResumo: RAZÕES: A neutropenia febril é uma complicação freqüente em pacientes tratados com quimioterapia. É potencialmente fatal e requer intervenção médica imediata. O tratamento padrão é feito com antibióticos (ATB) e cuidados gerais. Devido ao efeito conhecido de algumas citocinas (fatores estimuladores de colônias - FEC) em aumentar o número de neutrófilos circulantes, vários estudos clínicos avaliaram a relevância da adição de FEC no tratamento da neutropenia febril. Os resultados destes estudos são controversos e nenhuma conclusão definitiva pôde ser alcançada. Uma revisão sistemática da literatura é altamente recomendável para avaliar esta questão. MÉTODOS: Revisão sistemática e meta-análise de estudos clínicos randomizados que comparem o uso de FEC mais ATB contra ATB apenas no tratamento da neutropenia febril. Os resultados da meta-análise são expressos como Odds Ratio de Peto (OR) e Hazard Ratio (HR) com o correspondente intervalo de confiança de 95% (IC). Os desfechos clínicos avaliados são mortalidade (geral e relacionada à infecção), tempo de hospitalização, tempo para recuperação dos neutrófilos, tempo para resolução da febre, tempo para retirada dos antibióticos e efeitos colaterais. RESULTADOS: Mais de 9000 referências foram revistas. Treze estudos foram incluídos. A mortalidade geral não foi influenciada pelo uso de FEC [OR= 0,68; IC 95%= 0,43 a 1,08; p=0,1]. Um resultado significativo foi obtido na análise de mortalidade relacionada à infecção [OR= 0,51; IC95%= 0,26 a 1,00; p= 0,05], porém este resultado foi muito influenciado por um único estudo que teve uma alta proporção de mortes. Quando este estudo é excluído, um possível efeito do FEC desaparece [OR= 0,85; IC95%= 0,33 a 2,20; p= 0,7]. O grupo tratado com FEC teve um menor tempo de hospitalização [HR = 0,63; IC 95%= 0,49 a 0,82; p= 0,0006] e um menor tempo para recuperação dos neutrófilos [HR=0,32; IC 95%= 0,23 a 0,46; p < 0,00001]. CONCLUSÃO: Os dados deste estudo não validam o uso rotineiro do FEC em pacientes com neutropenia febril, quando o objetivo é reduzir mortalidade. Há porém um efeito significativo do FEC em reduzir o tempo de internaçãoAbstract: Colony Stimulating Factors for the Treatment of Febrile Neutropenia BACKGROUND: Febrile Neutropenia is a frequent event in cancer patients treated with chemotherapy. It is a potentially life threatening situation and requires prompt medical intervention. The standard treatment includes supportive care plus broad-spectrum antibiotics (ATB). Due to the known effect of some cytokines (colony stimulating factors CSF) on increase the numbers of circulating neutrophils, clinical studies have been done to evaluate their role on the treatment of febrile neutropenia. The results of these studies are, indeed, controversial. A systematic review is highly recommended to evaluate the role of CSF on the treatment of febrile neutropenia. METHODS: A systematic review of randomized controlled trials that compare the use of CSF plus ATB versus ATB alone on the treatment of febrile neutropenia. When appropriate, the results of individual studies were pooled on a meta-analysis. The pooled results are expressed as Peto's Odds Ratio (OR) and Hazard Ratio (HR) with the correspondent 95% confidence interval (CI). The outcomes evaluated are mortality (overall and infection related), time of hospitalization, time to neutrophil recover, time to defervecence time to withdrawals of antibiotics and side effects. RESULTS: more than 9000 references were screened. 13 studies were included. The overall mortality was not influenced by the use of CSF [OR= 0.68; CI95%= 0.43 to 1.08; p=O.I]. A significant result was obtained to the use of CSF on reducing infection related mortality [OR= 0.51; CI95% = 0.26 to 1.00 ;p=0.05], but this result was highly influenced by one study. When this study is excluded from our ana1ysis, this possible result disappears [OR= 0.85; CI95% = 0.33 to 2.20; p 0.7]. The group treated with CSF had a shorter time of hospitalization [HR= 0.63; CI 95%= 0.49 a 0.82; p=0.0006] and a shorter time to neutrophil recovering [HR= 0.32; CI 95%= 0.23 a 0.46; p < 0.00001]. CONCLUSION: The present data do not support a role of CSF on reducing mortality of patients with febrile neutropenia, but they have a positive influence on the time of hospitalizationDoutoradoMedicina InternaDoutor em Ciências Médica