Meta-analysis is of critical importance to decision makers to assess the comparative efficacy and safety of interventions and is integral to health technology assessment. A major problem for the ...meta-analysis of continuous outcomes is that associated variance data are not consistently reported in trial publications. The omission of studies from a meta-analysis due to incomplete reporting may introduce bias. The objectives of this study are to summarise and describe the methods used for handling missing variance data in meta-analyses in populations with type 2 diabetes mellitus (T2DM).
Electronic databases, Embase, MEDLINE, and the Cochrane Library (accessed June 2015), were systematically searched to identify meta-analyses of interventions in patients with T2DM. Eligible studies included those which analysed the change in HbA1c from baseline.
Sixty-seven publications reporting on meta-analyses of change in HbA1c from baseline in T2DM were identified. Approaches for dealing with missing variance data were reported in 41% of publications and included algebraic calculation, trial-level imputation, and no imputation.
Meta-analysis publications typically fail to report standardised approaches for dealing with missing variance data. While no particular imputation method is favoured, authors are discouraged from using a no-imputation approach. Instead, authors are encouraged to explore different approaches using sensitivity analyses and to improve the quality of reporting by documenting the methods used to deal with missing variance data.
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Meta-analysis is a growing approach to evidence synthesis and network meta-analysis in particular represents an important and developing method within Health Technology Assessment (HTA). ...Meta-analysis of survival data is usually performed using the individual summary statistic-the hazard ratio (HR) from each randomised controlled trial (RCT).
The objectives of this study are to: (i) review the methods and reporting of survival analyses in oncology RCTs; and (ii) assess the suitability and relevance of survival data reported in RCTs for inclusion into meta-analysis.
Five oncology journals were searched to identify Phase III RCTs published between April and July 2015. Eligible studies included those that analysed a survival outcome.
Thirty-two RCTs reporting survival outcomes in cancer populations were identified. None of the publications reported details relating to a strategy for statistical model building, the goodness of fit of the final model, or final model validation for the analysis of survival outcomes. The majority of studies (88%) reported the use of Cox proportional hazards (PH) regression to analyse survival endpoints. However, most publications failed to report the validation of the statistical models in terms of the PH assumption.
This review highlights deficiencies in terms of reporting the methods and validity of survival analyses within oncology RCTs. We support previous recommendations to encourage authors to improve the reporting of survival analyses in journal publications. We also recommend that the final choice of a statistical model for survival should be informed by goodness of model fit to a given dataset, and that model assumptions are validated. The failure of trial investigators and statisticians to investigate the PH for RCT survival data is likely to result in clinical decisions based on inappropriate methods. The development of alternative approaches for the meta-analysis of survival outcomes when the PH assumption is implausible is required if valid clinical decisions are to be made.
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Patients with atrial fibrillation are at a greater risk of stroke and therefore the main goal for treatment of patients with atrial fibrillation is to prevent stroke from occurring. There are a ...number of different stroke prevention treatments available to include warfarin and novel oral anticoagulants. Previous network meta-analyses of novel oral anticoagulants for stroke prevention in atrial fibrillation acknowledge the limitation of heterogeneity across the included trials but have not explored the impact of potentially important treatment modifying covariates.
To explore potentially important treatment modifying covariates using network meta-regression analyses for stroke prevention in atrial fibrillation.
We performed a network meta-analysis for the outcome of ischaemic stroke and conducted an exploratory regression analysis considering potentially important treatment modifying covariates. These covariates included the proportion of patients with a previous stroke, proportion of males, mean age, the duration of study follow-up and the patients underlying risk of ischaemic stroke.
None of the covariates explored impacted relative treatment effects relative to placebo. Notably, the exploration of 'study follow-up' as a covariate supported the assumption that difference in trial durations is unimportant in this indication despite the variation across trials in the network.
This study is limited by the quantity of data available. Further investigation is warranted, and, as justifying further trials may be difficult, it would be desirable to obtain individual patient level data (IPD) to facilitate an effort to relate treatment effects to IPD covariates in order to investigate heterogeneity. Observational data could also be examined to establish if there are potential trends elsewhere. The approach and methods presented have potentially wide applications within any indication as to highlight the potential benefit of extending decision problems to include additional comparators outside of those of primary interest to allow for the exploration of heterogeneity.
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D-cycloserine is an antibiotic which targets sequential bacterial cell wall peptidoglycan biosynthesis enzymes: alanine racemase and D-alanine:D-alanine ligase. By a combination of structural, ...chemical and mechanistic studies here we show that the inhibition of D-alanine:D-alanine ligase by the antibiotic D-cycloserine proceeds via a distinct phosphorylated form of the drug. This mechanistic insight reveals a bimodal mechanism of action for a single antibiotic on different enzyme targets and has significance for the design of future inhibitor molecules based on this chemical structure.
ObjectivesThe current systematic review (SR) was undertaken to identify and summarise the published literature reporting on the clinical and economic value of automated in-hospital pharmacy services ...with a primary focus on systems supporting the dispensing of medicines.MethodsLiterature searches were conducted in MEDLINE, Embase and the Cochrane Library on 17 December 2017 to identify English-language publications investigating any automated dispensing systems (ADSs) in the inpatient setting to include central pharmacy and ward-based systems.Results4320 publications were screened by title and abstract and 45 of 175 full publications screened were included. Grey literature searching identified an additional three publications. Therefore, 48 publications relating to ADSs were eligible for inclusion. Although a relatively large evidence base was identified as part of the current SR, the eligible studies were inconsistent in terms of their design and the format of reporting of outcomes. The studies demonstrate that both pharmacy and ward-based ADSs offer benefits over traditional manual dispensing methods in terms of clinical and economic outcomes. The primary benefits following implementation of an ADS include reductions in medication errors, medication administration time and costs. Studies examining optimisation/inventory management strategies/refill programmes for these systems suggest that optimal implementation of the ADS is required to ensure that clinical success and economic benefits are maximised.ConclusionsThe published evidence suggests positive impacts of ADS and should encourage hospitals to invest in automation, with a global strategy to improve the reliability and the efficiency of the medication process. However, one of the key findings of the current SR is the need for further data from adequately powered studies reporting clinically relevant outcomes which would allow for robust, evidence-based recommendations on the return on investment of the technologies. These studies would probably contribute to a larger adoption of these technologies by European hospitals.
An overall survival (OS) network meta-analysis was conducted for fulvestrant 500 mg versus alternative therapies for postmenopausal, estrogen receptor-positive advanced breast cancer after endocrine ...therapy failure. The results suggested improved OS for fulvestrant 500 mg versus fulvestrant 250 mg and megestrol acetate 40 mg and similar OS (numerical advantages) to other comparators in the study.
We conducted a review of randomized trials to compare the overall survival (OS) with fulvestrant 500 mg versus alternative treatment for estrogen receptor-positive advanced breast cancer following endocrine therapy failure.
Hazard ratios (HRs) were obtained by modeling OS data with the Weibull distribution. A fixed-effect Bayesian network meta-analysis was conducted. The evidence network included anastrozole 1 mg, letrozole 2.5 mg, fulvestrant 250 mg, exemestane 25 mg, megestrol acetate 40 mg, and everolimus 10 mg plus exemestane 25 mg as comparators. Post-antiestrogen and post-aromatase inhibitor subgroup networks were analyzed.
In the overall analysis, the HRs suggested improved OS for fulvestrant 500 mg versus fulvestrant 250 mg and megestrol acetate 40 mg, and numerically favorable differences with fulvestrant 500 mg versus other comparators. In the antiestrogen subgroup, the HRs suggested improved OS for fulvestrant 500 mg versus fulvestrant 250 mg and megestrol acetate 40 mg; numerical differences in the HRs were seen versus anastrozole 1 mg and letrozole 2.5 mg. In the aromatase inhibitor subgroup, the HRs for OS numerically favored fulvestrant 500 mg versus fulvestrant 250 mg and exemestane 25 mg.
Acknowledging the limitations of the present network meta-analysis, these findings suggest that fulvestrant 500 mg might provide improved OS versus fulvestrant 250 mg and megestrol acetate 40 mg for treatment of estrogen receptor-positive ABC following endocrine therapy failure. Although OS efficacy versus everolimus 10 mg plus exemestane 25 mg (for overall evidence network), anastrozole 1 mg, exemestane 25 mg, and letrozole 2.5 mg is numerically favorable, additional studies are required to draw formal conclusions.
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The introduction of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has improved the outlook for patients with advanced non-small-cell lung cancer (NSCLC) with
+ mutations. ...However, most patients develop resistance, with the result that median progression-free survival (PFS) iŝ12 months. Combining EGFR-TKIs with other agents, such as bevacizumab, is a promising approach to prolonging remission. This systematic review and network meta-analysis (NMA) were undertaken to assess available evidence regarding the benefits of first-line combination therapy involving EGFR-TKIs in patients with advanced NSCLC.
Literature searches were performed using relevant search terms. Study-level pseudo-individual patient-level data (IPD) were recreated from digitized Kaplan-Meier curve data, using a published algorithm. Study IPD were analyzed using both the proportional hazards and the acceleration failure time (AFT) survival models, and it was concluded that the AFT model was most appropriate. An NMA was performed based on acceleration factors (AFs) using a Bayesian framework to compare EGFR-TKIs and chemotherapy.
Nine randomized controlled trials were identified that provided data for EGFR-TKI therapy in patients with
+ tumors. These included studies of afatinib (n=3), erlotinib (n=3), erlotinib plus bevacizumab (n=1) and gefitinib (n=2). Erlotinib plus bevacizumab produced the greatest increase in PFS compared with chemotherapy, with 1/AF being 0.24 (95% credible interval CrI 0.17, 0.34). This combination also produced greater increases in PFS compared with EGFR-TKI monotherapy: 1/AF versus afatinib, 0.51 (95% CrI 0.35, 0.73); versus erlotinib, 0.53 (95% CrI 0.39, 0.72) and versus gefitinib, 0.46 (95% CrI 0.32, 0.66). All three EGFR-TKI monotherapies prolonged PFS compared with chemotherapy; estimates of treatment effect ranged from 1/AF 0.53 (95% CrI 0.48, 0.60) for gefitinib to 1/AF 0.46 (95% CrI 0.40, 0.53) for erlotinib. There was no evidence for differences between EGFR-TKI monotherapies, as all 95% CrIs included the null value.
Although data for erlotinib plus bevacizumab came from a single Phase 2 study, the results of the NMA suggest that adding bevacizumab to erlotinib may be a promising approach to improving the outcomes achieved with EGFR-TKI monotherapy in patients with advanced
+ NSCLC.
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The Van enzymes are ATP-dependant ligases responsible for resistance to vancomycin in
Staphylococcus aureus and
Enteroccoccus species. The
de novo molecular design programme SPROUT was used in ...conjunction with the X-ray crystal structure of
Enterococcus faecium
d-alanyl-
d-lactate ligase (VanA) to design new putative inhibitors based on a hydroxyethylamine template. The two best ranked structures were selected and efficient syntheses developed. The inhibitory activities of these molecules were determined on
E. faecium VanA, and due to structural similarity and a common reaction mechanism, also on
d-Ala-
d-Ala ligase (DdlB) from
Escherichia coli. The phosphate group attached to the hydroxyl moiety of the hydroxyethylamine isostere within these systems is essential for their inhibitory activity against both VanA and DdlB.
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Chronic myeloid leukemia (CML) is a myeloproliferative disorder of blood stem cells. The tyrosine kinase inhibitor (TKI) imatinib was the first targeted therapy licensed for patients with ...chronic-phase CML, and its introduction was associated with substantial improvements in response and survival compared with previous therapies. Clinical trial data are now available for the second-generation TKIs (nilotinib, dasatinib, and bosutinib) in the first-, second-, and third-line settings. A qualitative systematic review was conducted to qualitatively compare the clinical effectiveness, safety, and effect on quality of life of TKIs for the management of chronic-, accelerated-, or blast-phase CML patients.
Included studies were identified through a search of electronic databases in September 2011, relevant conference proceedings and the grey literature.
In the first-line setting, the long-term efficacy (up to 8 years) of imatinib has been confirmed in a single randomized controlled trial (International Randomized Study of Interferon IRIS). All second-generation TKIs reported lower rates of transformation, and comparable or superior complete cytogenetic response (CCyR), major molecular response (MMR), and complete molecular response rates compared with imatinib by 2-year follow-up. Each of the second-generation TKIs was associated with a distinct adverse-event profile. Bosutinib was the only second-generation TKI to report quality-of-life data (no significant difference compared with imatinib treatment). Data in the second- and third-line setting confirmed the efficacy of the second-generation TKIs in either imatinib-resistant or -intolerant patients, as measured by CCyR and MMR rates.
Data from first-line randomized controlled trials reporting up to 2-year follow-up indicate superior response rates of the second-generation TKIs compared with imatinib. Current evidence from single-arm studies in the second-line setting confirm that nilotinib, dasatinib, and bosutinib are valuable treatment options for the significant subgroup of patients who are intolerant or resistant to imatinib treatment.
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