Atezolizumab in Combination with Bevacizumab for the Management of Patients with Hepatocellular Carcinoma in the First-Line Setting: Systematic Literature Review and Meta-Analysis.

Background: In 2020, atezolizumab-bevacizumab became the new standard of care (SOC) for first-line unresectable hepatocellular carcinoma (HCC) patients, following a decade where sorafenib was the preferred first-line treatment. In the last few years, a number of novel systemic treatments with non-inferiority and superiority to sorafenib have been approved as first-line treatments. Objectives: The objective of this systematic literature review (SLR) and network meta-analysis (NMA) was to compare randomised controlled trial evidence for atezolizumab-bevacizumab with globally relevant pharmacological comparators for first-line treatment of patients with unresectable HCC. Methods: Randomised controlled trials investigating first-line treatment of HCC in adults with no prior systemic treatment were eligible for inclusion into the SLR and were retrieved from Embase, MEDLINE, and Evidence-Based Medicine (EBM) Reviews. Interventions of interest for the NMA included atezolizumab-bevacizumab, sorafenib, lenvatinib, durvalumab (including in combination with tremelimumab), cabozantinib (including in combination with atezolizumab), camrelizumab (including in combination with rivoceranib), pembrolizumab (including in combination with lenvatinib), and tislelizumab. Random effects NMA was conducted for survival endpoints within a Bayesian framework with an informative prior distribution for between-study heterogeneity. The hazard ratios for relative treatment effect were estimated with 95% credible intervals (CrIs). Results: The SLR identified 49 studies, of which eight formed a connected evidence network permitting the indirect treatment comparison of atezolizumab-bevacizumab with comparators of interest. The indirect comparisons suggested an improved overall survival (OS) with atezolizumab-bevacizumab versus most comparators. All indirect treatment comparison results for atezolizumab-bevacizumab included the null value within the 95% CrI (n = 1) for OS and progression-free survival (PFS). Conclusions: The results of the NMA indicate atezolizumab-bevacizumab is associated with superior or comparable OS and PFS together with a manageable safety profile compared with globally relevant comparators in the unresected HCC indication. The findings support that atezolizumab-bevacizumab remains SOC for the management of first-line unresectable HCC patients.

Systematic Literature Review of the Natural History of Spinal Muscular Atrophy: Motor Function, Scoliosis, and Contractures.

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder associated with continuous motor function loss and complications, such as scoliosis and contractures. Understanding the natural history of SMA is key to demonstrating the long-term outcomes of SMA treatments. This study reviews the natural history of motor function, scoliosis, and contractures in patients with SMA. METHODS: Electronic databases were searched from inception to June 27, 2022 (Embase, MEDLINE, and Evidence-Based Medicine Reviews). Observational studies, case-control studies, cross-sectional studies, and case series reporting on motor function (i.e., sitting, standing, and walking ability), scoliosis, and contracture outcomes in patients with types 1-3 SMA were included. Data on study design, baseline characteristics, and treatment outcomes were extracted. Data sets were generated from studies that reported Kaplan-Meier (KM) curves and pooled to generate overall KM curves. RESULTS: Ninety-three publications were included, of which 68 reported on motor function. Of these, 10 reported KM curves (3 on the probability of sitting in patients with types 2 and 3 SMA and 8 on the probability of walking/ambulation in patients with type 3 SMA). The median time to loss of sitting (95% CI) was 14.5 years (14.1-31.5) for the type 2 SMA sitter population (their maximum ability was independent sitting). The median time to loss of ambulation (95% CI) was 13.4 years (12.5-14.5) for type 3a SMA (disease onset at age younger than 3 years) and 44.2 years (43.0-49.4) for type 3b SMA (disease onset at age 3 years or older). Studies including scoliosis and contracture outcomes mostly reported non-time-to-event data. DISCUSSION: The results demonstrate that a high degree of motor function loss is inevitable, affecting patients of all ages. In addition, data suggest that untreated patients with types 2 and 3 SMA remain at risk of losing motor milestones during late adulthood, and patients with types 3a and 3b SMA are at risk of loss of ambulation over time. These findings support the importance of stabilization of motor function development even at older ages. Natural history data are key for the evaluation of SMA treatments as they contextualize the assessment of long-term outcomes.

Semaglutide 2.4 Mg for the Management of Overweight and Obesity: Systematic Literature Review and Meta-Analysis.

Purpose: Semaglutide has demonstrated safe and effective weight loss for overweight and obesity, including participants with concomitant type 2 diabetes mellitus (T2DM), in randomized placebo-controlled trials (RCTs). We conducted a systematic literature review (SLR) and network meta-analyses (NMA) to compare weekly semaglutide 2.4 mg with pharmacological comparators for weight management in overweight or obesity. Methods: The SLR was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist. NMAs were performed to compare weight change for semaglutide 2.4 mg with comparators using data identified in the SLR. The populations of interest were total population, normal glucose tolerance, non-T2DM, pre-diabetes, and T2DM. Included outcomes were weight change from baseline (CFB, %) at 52 weeks and proportion of participants losing ≥5% baseline fasting body weight at 12 weeks (at full therapeutic dose). Results: The SLR identified 108 RCTs examining non-surgical interventions, of which 41 were considered for inclusion in the NMAs. In all populations, semaglutide 2.4 mg was associated with a greater percentage weight CFB with 52 weeks of treatment versus all available comparators. In all populations, semaglutide was associated with a higher likelihood of participants losing ≥5% of baseline fasting body weight at 12 weeks versus all available comparators. Conclusion: In NMA, semaglutide 2.4 mg demonstrated effective weight loss (≥5%) in the total population and all subpopulations of glucose tolerance versus active comparators. Semaglutide is an effective treatment that may address unmet need in the management of overweight and obesity.

Efficacy and safety of VNS therapy or continued medication management for treatment of adults with drug-resistant epilepsy: systematic review and meta-analysis.

Vagus nerve stimulation (VNS) Therapy® is an adjunctive neurostimulation treatment for people with drug-resistant epilepsy (DRE) who are unwilling to undergo resective surgery, have had unsuccessful surgery or are unsuitable for surgery. A systematic review and meta-analysis were conducted to determine the treatment effects of VNS Therapy as an adjunct to anti-seizure medications (ASMs) for the management of adults with DRE. A literature search was performed in August 2020 of the Medline®, Medline® Epub Ahead of Print, Embase, and the Cochrane library databases. Outcomes examined included reduction in seizure frequency, seizure freedom, ASM load, discontinuations, and serious adverse events (SAEs). Comparators included best medical practice, ASMs, low-stimulation or sham VNS Therapy. Four RCTs and six comparative observational studies were identified for inclusion. Against comparators, individuals treated with VNS had a significantly better odds of experiencing a ≥ 50% reduction in seizure frequency (OR: 2.27 [95% CI 1.47, 3.51]; p = 0.0002), a ≥ 75% reduction in seizure frequency (OR: 3.56 [95% CI 1.59, 7.98]; p = 0.002) and a reduced risk for increased ASM load (risk ratio: 0.36 [95% CI 0.21, 0.62]; p = 0.0002). There was no difference in the odds of discontinuation or the rate of SAEs between VNS versus comparators. This meta-analysis demonstrated the benefits of VNS Therapy in people with DRE, which included improvement in seizure frequency without an increase in the rate of SAEs or discontinuations, thereby supporting the consideration of VNS Therapy for people who are not responding to ASMs and those unsuitable or unwilling to undergo surgery.

Meta-Analysis Comparing Apixaban Versus Rivaroxaban for Management of Patients With Nonvalvular Atrial Fibrillation.

To compare the efficacy and safety of apixaban and rivaroxaban for the prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF) by way of a meta-analysis informed by real-world evidence. Systematic review and meta-analysis of observational studies including patients with NVAF on apixaban and rivaroxaban, which reported stroke/systemic embolism and/or major bleeding. Prospero registration number: CRD42021251719. Estimates of relative treatment effect (based on hazard ratios[HRs]) were pooled using the inverse variance method. Fixed-effects and random effect analyses were conducted. Exploratory meta-regression analyses that included study-level covariates were conducted using the metareg (meta-regression) command of Stata Statistical Software: Release 15.1 (College Station, Texas. StataCorp LLC.). Study level covariates explored in the meta-regression analyses were CHA2DS2-VASc and HAS-BLED scores. A total of 10 unique retrospective real-world evidence studies reported comparative estimates for apixaban versus rivaroxaban in patients with NVAF and were included in the meta-analysis. Adjusted HR was 0.88 (95% [confidence interval] CI 0.81 to 0.95), indicating a significantly lower hazard of stroke/systemic embolism associated with apixaban versus rivaroxaban. Pairwise meta-analysis for a major bleeding episode was significantly lower with apixaban compared with rivaroxaban (HR 0.62; 95% CI 0.56 to 0.69), whereas apixaban was associated with a lower risk of gastrointestinal bleeding compared with rivaroxaban (HR 0.57; 95% CI 0.50 to 0.64). In conclusion, this study suggests that patient CHA2DS2-VASc and HAS-BLED scores might be an important factor when selecting which direct oral anticoagulants to use, given the relation these scores have on treatment outcomes. Apixaban is associated with lower rates of both major and gastrointestinal bleeding than rivaroxaban, with no loss of efficacy.

Automation of in-hospital pharmacy dispensing: a systematic review.

OBJECTIVES: The 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. METHODS: Literature 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. RESULTS: 4320 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. CONCLUSIONS: The 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.

Automated compounding technology and workflow solutions for the preparation of chemotherapy: a systematic review.

OBJECTIVES: The current systematic review (SR) was undertaken to summarise the published literature reporting the clinical and economic value of automation for chemotherapy preparation management to include compounding workflow software and robotic compounding systems. METHODS: Literature searches were conducted in MEDLINE, Embase and the Cochrane Library on 16 November 2017 to identify publications investigating chemotherapy compounding workflow software solutions used in a hospital pharmacy for the preparation of chemotherapy. RESULTS: 5175 publications were screened by title and abstract and 18 of 72 full publications screened were included. Grey literature searching identified an additional seven publications. The SR identified 25 publications relating to commercial technologies for compounding (Robotic compounding systems: APOTECAchemo (n=12), CytoCare (n=5) and RIVA (n=1); Workflow software: Cato (n=6) and Diana (n=1)). The studies demonstrate that compounding technologies improved accuracy in dose preparations and reduced dose errors compared with manual compounding. Comparable levels of contamination were reported for technologies compared with manual compounding. The compounding technologies were associated with reductions in annual costs compared with manual compounding, but the impact on compounding times was not consistent and was dependent on the type of compounding technology. CONCLUSIONS: The published evidence suggests that the implementation of chemotherapy compounding automation solutions may reduce compounding errors and reduce costs; however, this is highly variable depending on the form of automation. In addition, the available evidence is heterogeneous, sparse and inconsistently reported. A key finding from the current SR is a 'call to action' to encourage pharmacists to publish data following implementation of chemotherapy compounding technologies in their hospital, which would allow for evidence-based recommendations on the benefits of chemotherapy compounding technologies.

Systematic review of neurotrophic tropomyosin-related kinase inhibition as a tumor-agnostic management strategy.

Aim: To conduct a systematic review and meta-analysis feasibility of clinical, quality of life and economic evidence for neurotrophic tropomyosin-related receptor tyrosine kinases (NTRK) inhibitors in patients with NTRK gene fusion-positive tumors. Materials & methods: Databases were searched for studies on NTRK inhibitors in adult and pediatric patients. Results: 27 publications reported clinical data for seven interventions. Efficacy/safety data were available for two interventions only. Four trials each reported data for larotrectinib and entrectinib with pooled analyses reporting objective response rates of 75% (95% CI: 61-85) and 57.4% (43.2-70.8), respectively. No publications reported economic or quality of life evidence. Conclusion: Preliminary data demonstrate that NTRK inhibitors are well tolerated and show impressive clinical benefit; corroboration of existing studies and real-world data are required.

Inhibition of D-Ala:D-Ala ligase through a phosphorylated form of the antibiotic D-cycloserine.

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.

Tyrosine kinase inhibitor combination therapy in first-line treatment of non-small-cell lung cancer: systematic review and network meta-analysis.

INTRODUCTION: 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 EGFR+ mutations. However, most patients develop resistance, with the result that median progression-free survival (PFS) is12 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. METHODS: 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. RESULTS: Nine randomized controlled trials were identified that provided data for EGFR-TKI therapy in patients with EGFR+ 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. CONCLUSION: 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 EGFR+ NSCLC.

Three-dimensional evidence network plot system: covariate imbalances and effects in network meta-analysis explored using a new software tool.

OBJECTIVES: The aim of the study was to develop the three-dimensional (3D) evidence network plot system-a novel web-based interactive 3D tool to facilitate the visualization and exploration of covariate distributions and imbalances across evidence networks for network meta-analysis (NMA). STUDY DESIGN AND SETTING: We developed the 3D evidence network plot system within an AngularJS environment using a third party JavaScript library (Three.js) to create the 3D element of the application. Data used to enable the creation of the 3D element for a particular topic are inputted via a Microsoft Excel template spreadsheet that has been specifically formatted to hold these data. We display and discuss the findings of applying the tool to two NMA examples considering multiple covariates. These two examples have been previously identified as having potentially important covariate effects and allow us to document the various features of the tool while illustrating how it can be used. RESULTS: The 3D evidence network plot system provides an immediate, intuitive, and accessible way to assess the similarity and differences between the values of covariates for individual studies within and between each treatment contrast in an evidence network. In this way, differences between the studies, which may invalidate the usual assumptions of an NMA, can be identified for further scrutiny. Hence, the tool facilitates NMA feasibility/validity assessments and aids in the interpretation of NMA results. CONCLUSION: The 3D evidence network plot system is the first tool designed specifically to visualize covariate distributions and imbalances across evidence networks in 3D. This will be of primary interest to systematic review and meta-analysis researchers and, more generally, those assessing the validity and robustness of an NMA to inform reimbursement decisions.

A Systematic Review of Methods for Handling Missing Variance Data in Meta-Analyses of Interventions in Type 2 Diabetes Mellitus.

AIMS: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Exploratory Network Meta Regression Analysis of Stroke Prevention in Atrial Fibrillation Fails to Identify Any Interactions with Treatment Effect.

BACKGROUND: 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. OBJECTIVES: To explore potentially important treatment modifying covariates using network meta-regression analyses for stroke prevention in atrial fibrillation. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Review of the Reporting of Survival Analyses within Randomised Controlled Trials and the Implications for Meta-Analysis.

BACKGROUND: 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). OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Network Meta-Analysis Comparing Overall Survival for Fulvestrant 500 mg Versus Alternative Therapies for Treatment of Postmenopausal, Estrogen Receptor-Positive Advanced Breast Cancer Following Failure on Prior Endocrine Therapy.

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Relative efficacy and safety of non-Vitamin K oral anticoagulants for non-valvular atrial fibrillation: Network meta-analysis comparing apixaban, dabigatran, rivaroxaban and edoxaban in three patient subgroups.

BACKGROUND: Stroke is the most serious clinical consequence of atrial fibrillation, which is the most common cardiac arrhythmia. Non-vitamin K antagonist oral anticoagulants (NOACs) have emerged as efficacious, safe and convenient stroke prevention agents. This updated network meta-analysis focused on the relative efficacy and safety of apixaban compared with dabigatran, rivaroxaban and edoxaban for stroke prevention in (i) patients with CHADS2 score ≥ 2, (ii) secondary stroke prevention, and (iii) patients with high quality anticoagulation control with warfarin. METHODS AND RESULTS: A fixed-effects network meta-analysis was conducted, including data from four Phase III randomised controlled trials (> 70,000 patients with non-valvular atrial fibrillation). The results of the base-case analysis comparing NOACs with warfarin were broadly in line with the results from the individual trials. Results from the three subgroup analyses were broadly similar to the base case results. For example in patients with CHADS2 score ≥ 2, apixaban, high-dose dabigatran, rivaroxaban, and high-dose edoxaban had significantly lower hazards of stroke/systemic embolism compared with low-dose edoxaban. Apixaban and low-dose edoxaban were associated with significantly lower hazards of major bleeding compared with rivaroxaban and dabigatran 150 mg. However, several treatment comparisons that were significant in the base-case analysis were not significant in the patient subgroups, due to the reduced sample size of the subgroups compared with the overall population. CONCLUSIONS: Among the NOACs, apixaban offered the most favourable efficacy and safety profile in the overall patient population as well as in the three subgroups investigated.

Treatments for chronic myeloid leukemia: a qualitative systematic review.

BACKGROUND: 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. METHODS: Included studies were identified through a search of electronic databases in September 2011, relevant conference proceedings and the grey literature. RESULTS: 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. CONCLUSION: 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.

Crystallization and preliminary X-ray analysis of a D-alanyl-D-alanine ligase (EcDdlB) from Escherichia coli.

A recombinant form of Escherichia coli DdlB (EcDdlB) has been prepared and cocrystallized with ADP and D-alanyl-D-alanine to represent the ternary complex of EcDdlB. Furthermore, EcDdlB has been cocrystallized under the same conditions with the ligands ATP and D-alanyl-D-alanine, representing the product-inhibited complex. The crystals belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 53.0, b = 97.6, c = 109.5 A and a = 51.2, b = 97.8, c = 110.1 A, respectively, and both contained two molecules in the asymmetric unit. Complete data sets were collected to 1.5 and 1.4 A resolution, respectively, from single crystals under cryogenic conditions using synchrotron radiation.

Design and synthesis of new hydroxyethylamines as inhibitors of D-alanyl-D-lactate ligase (VanA) and D-alanyl-D-alanine ligase (DdlB).

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 faeciumd-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.