Dasatinib, nilotinib and standard-dose imatinib for the first line treatment of chronic myeloid leukaemia: Systematic reviews and economic analyses

- Background Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML). - Objective This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML. - Data sources Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011. - Review methods A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis. - Results Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY. - Limitations Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions. - Conclusions From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML. - Funding The Health Technology Assessment Programme of the National Institute for Health Research.

Complete cytogenetic response and major molecular response as surrogate outcomes for overall survival in first-line treatment of chronic myelogenous leukemia: A case study for technology appraisal on the basis of surrogate outcomes evidence

Objectives In 2012, the National Institute for Health and Care Excellence assessed dasatinib, nilotinib, and standard-dose imatinib as first-line treatment of chronic phase chronic myelogenous leukemia (CML). Licensing of these alternative treatments was based on randomized controlled trials assessing complete cytogenetic response (CCyR) and major molecular response (MMR) at 12 months as primary end points. We use this case study to illustrate the validation of CCyR and MMR as surrogate outcomes for overall survival in CML and how this evidence was used to inform National Institute for Health and Care Excellence’s recommendation on the public funding of these first-line treatments for CML. Methods We undertook a systematic review and meta-analysis to quantify the association between CCyR and MMR at 12 months and overall survival in patients with chronic phase CML. We estimated life expectancy by extrapolating long-term survival from the weighted overall survival stratified according to the achievement of CCyR and MMR. Results Five studies provided data on the observational association between CCyR or MMR and overall survival. Based on the pooled association between CCyR and MMR and overall survival, our modeling showed comparable predicted mean duration of survival (21–23 years) following first-line treatment with imatinib, dasatinib, or nilotinib. Conclusions This case study illustrates the consideration of surrogate outcome evidence in health technology assessment. Although it is often recommended that the acceptance of surrogate outcomes be based on randomized controlled trial data demonstrating an association between the treatment effect on both the surrogate outcome and the final outcome, this case study shows that policymakers may be willing to accept a lower level of evidence (i.e., observational association).

Computational methods for Bayesian model choice

In this note, we shortly survey some recent approaches on the approximation of the Bayes factor used in Bayesian hypothesis testing and in Bayesian model choice. In particular, we reassess importance sampling, harmonic mean sampling, and nested sampling from a unified perspective.

The use of neurocognitive methods in assessing health communication messages: A systematic review

We review 20 studies that examined persuasive processing and outcomes of health messages using neurocognitive measures. The results suggest that cognitive processes and neural activity in regions thought to reflect self-related processing may be more prominent in the persuasive process of self-relevant messages. Furthermore, activity in the medial prefrontal cortex (MPFC), the superior temporal gyrus, and the middle frontal gyrus were identified as predictors of message effectiveness, with the MPFC accounting for additional variance in behaviour change beyond that accounted for by self-report measures. Incorporating neurocognitive measures may provide a more comprehensive understanding of the processing and outcomes of health messages.

Water, water everywhere: Dehydration in the midst of plenty: An observational study of barriers and enablers to adequate hydration in older hospitalized patients

While dehydration is common in older patients and is associated with poor outcomes, it has been infrequently studied in the hospital setting. Thus, the aim of this study was to identify potential barriers and enablers to the maintenance of adequate hydration in older patients in an acute hospital environment. An observational study, involving patients aged 60 years and older admitted to an acute care hospital in Queensland, Australia, was undertaken. Forty-four patients were observed during mealtimes, and chart and room audits were performed to identify hydration management strategies, weight records and the presence or absence of fluid balance charts. Results revealed a number of system and practice-related barriers including patient difficulties with opening fluid containers and low levels of documentation of hydration management strategies. Addressing these issues is an important first step towards improving the management of hydration in medically ill older hospital patients.

Developing standardized methods to assess cost of healthy and unhealthy (current) diets in Australia

Unhealthy diets contribute at least 14% to Australia's disease burden and are driven by ‘obesogenic’ food environments. Compliance with dietary recommendations is particularly poor amongst disadvantaged populations including low socioeconomic groups, those living in rural/remote areas and Aboriginal and Torres Strait Islanders. The perception that healthy foods are expensive is a key barrier to healthy choices and a major determinant of diet-related health inequities. Available state/regional/local data (limited and non-comparable) suggests that, despite basic healthy foods not incurring GST, the cost of healthy food is higher and has increased more rapidly than unhealthy food over the last 15 years in Australia. However, there were no nationally standardised tools or protocols to benchmark, compare or monitor food prices and affordability in Australia. Globally, we are leading work to develop and test approaches to assess the price differential of healthy and less-healthy (current) diets under the food price module of the International Network for Food and Obesity/non-communicable diseases (NCDs) Research, Monitoring and Action Support (INFORMAS). This presentation describes contextualization of the INFORMAS approach to develop standardised Australian tools, survey protocols and data collection and analysis systems. The ‘healthy diet basket’ was based on the Australian Foundation Diet, 1 The ‘current diet basket’ and specific items included in each basket, were based on recent national dietary survey data.2 Data collection methods were piloted. The final tools and protocols were then applied to measure the price and affordability of healthy and less healthy (current) diets of different household groups in diverse communities across the nation. We have compared results for different geographical locations/population subgroups in Australia and assessed these against international INFORMAS benchmarks. The results inform the development of policy and practice, including those relevant to mooted changes to the GST base, to promote nutrition and healthy weight and prevent chronic disease in Australia.

Light exposure and eye growth in childhood

PURPOSE The purpose of this study was to examine the relationship between objectively measured ambient light exposure and longitudinal changes in axial eye growth in childhood. METHODS A total of 101 children (41 myopes and 60 nonmyopes), 10 to 15 years of age participated in this prospective longitudinal observational study. Axial eye growth was determined from measurements of ocular optical biometry collected at four study visits over an 18-month period. Each child’s mean daily light exposure was derived from two periods (each 14 days long) of objective light exposure measurements from a wrist-worn light sensor. RESULTS Over the 18-month study period, a modest but statistically significant association between greater average daily light exposure and slower axial eye growth was observed (P ¼ 0.047). Other significant predictors of axial eye growth in this population included children’s refractive error group (P < 0.001), sex (P < 0.01), and age (P < 0.001). Categorized according to their objectively measured average daily light exposure and adjusting for potential confounders (age, sex, baseline axial length, parental myopia, nearwork, and physical activity), children experiencing low average daily light exposure (mean daily light exposure: 459 6 117 lux, annual eye growth: 0.13 mm/y) exhibited significantly greater eye growth than children experiencing moderate (842 6 109 lux, 0.060 mm/y), and high (1455 6 317 lux, 0.065 mm/y) average daily light exposure levels (P ¼ 0.01). CONCLUSIONS In this population of children, greater daily light exposure was associated with less axial eye growth over an 18-month period. These findings support the role of light exposure in the documented association between time spent outdoors and childhood myopia.

Longitudinal changes in choroidal thickness and eye growth in childhood

PURPOSE To examine longitudinal changes in choroidal thickness and axial length in a population of children with a range of refractive errors. METHODS One hundred and one children (41 myopes and 60 nonmyopes) aged 10 to 15 years participated in this prospective, observational longitudinal study. For each child, 6-month measures of choroidal thickness (using enhanced depth imaging optical coherence tomography) and axial ocular biometry were collected four times over an 18-month period. Linear mixed-models were used to examine the longitudinal changes in choroidal thickness and the relationship between changes in choroidal thickness and axial eye growth over the study period. RESULTS A significant group mean increase in subfoveal choroidal thickness was observed over 18 months (mean increase 13 6 22 lm, P < 0.001). Myopic children exhibited significantly thinner choroids compared with nonmyopic children (P < 0.001), although there was no significant time by refractive group interaction (P ¼ 0.46), indicating similar changes in choroidal thickness over time in myopes and nonmyopes. However, a significant association between the change in choroidal thickness and the change in axial length over time was found (P < 0.001, β = −0.14). Children showing faster axial eye growth exhibited significantly less choroidal thickening over time compared with children showing slower axial eye growth. CONCLUSIONS A significant increase in choroidal thickness occurs over an 18-month period in normal 10- to 15-year-old children. Children undergoing faster axial eye growth exhibited less thickening and, in some cases, a thinning of the choroid. These findings support a potential role for the choroid in the mechanisms regulating eye growth in childhood.

Change to costs and lengths of stay in the emergency department and the Brisbane protocol: An observational study

- Objective To compare health service cost and length of stay between a traditional and an accelerated diagnostic approach to assess acute coronary syndromes (ACS) among patients who presented to the emergency department (ED) of a large tertiary hospital in Australia. - Design, setting and participants This historically controlled study analysed data collected from two independent patient cohorts presenting to the ED with potential ACS. The first cohort of 938 patients was recruited in 2008–2010, and these patients were assessed using the traditional diagnostic approach detailed in the national guideline. The second cohort of 921 patients was recruited in 2011–2013 and was assessed with the accelerated diagnostic approach named the Brisbane protocol. The Brisbane protocol applied early serial troponin testing for patients at 0 and 2 h after presentation to ED, in comparison with 0 and 6 h testing in traditional assessment process. The Brisbane protocol also defined a low-risk group of patients in whom no objective testing was performed. A decision tree model was used to compare the expected cost and length of stay in hospital between two approaches. Probabilistic sensitivity analysis was used to account for model uncertainty. - Results Compared with the traditional diagnostic approach, the Brisbane protocol was associated with reduced expected cost of $1229 (95% CI −$1266 to $5122) and reduced expected length of stay of 26 h (95% CI −14 to 136 h). The Brisbane protocol allowed physicians to discharge a higher proportion of low-risk and intermediate-risk patients from ED within 4 h (72% vs 51%). Results from sensitivity analysis suggested the Brisbane protocol had a high chance of being cost-saving and time-saving. - Conclusions This study provides some evidence of cost savings from a decision to adopt the Brisbane protocol. Benefits would arise for the hospital and for patients and their families.

Critical Discourse Analysis research methods for the English classroom

Critical Discourse Analysis (CDA) is an approach to analysing the discourses that operate in social contexts, such as classrooms in schools, and their material effects on people, such as teachers and learners. CDA offers a range of ways of engaging with the relationship between texts in context and the power they exercise. In this article, I overview key approaches and provide detail of Fairclough’s (1992, 2003) textually-oriented, linguistic method of CDA, with an example from my own research. I offer a challenge for English teachers, as researchers, to ‘make strange’ the familiar world of their classroom work, and in so doing, identify possibilities for productive change.

The doctrinal method: Incorporating interdisciplinary methods in reforming the law

The doctrinal methodology is in a period of change and transition. Realising that the scope of the doctrinal method is too constricting, academic lawyers are becoming eclectic in their use of research method. In this transitional time, legal scholars are increasingly infusing evidence (and methods) from other disciplines into their reasoning to bolster their reform recommendations. This article considers three examples of the interplay of the discipline of law with other disciplines in the pursuit of law reform. Firstly the article reviews studies on the extent of methodologies and reformist frameworks in PhD research in Australia. Secondly it analyses a ‘snapshot’ of recently published Australian journal articles on criminal law reform. Thirdly, it focuses on the law reform commissions, those independent government committees that play such an important role in law reform in common law jurisdictions. This examination demonstrates that while the doctrinal core of legal scholarship remains intact, legal scholars are endeavouring to accommodate statistics, comparative perspectives, social science evidence and methods, and theoretical analysis, within the legal research framework, in order to provide additional ballast to the recommendations for reform.

Effect of temperature and precipitation on salmonellosis cases in South-East Queensland, Australia: An observational study

Objective Foodborne illnesses in Australia, including salmonellosis, are estimated to cost over $A1.25 billion annually. The weather has been identified as being influential on salmonellosis incidence, as cases increase during summer, however time series modelling of salmonellosis is challenging because outbreaks cause strong autocorrelation. This study assesses whether switching models is an improved method of estimating weather–salmonellosis associations. Design We analysed weather and salmonellosis in South-East Queensland between 2004 and 2013 using 2 common regression models and a switching model, each with 21-day lags for temperature and precipitation. Results The switching model best fit the data, as judged by its substantial improvement in deviance information criterion over the regression models, less autocorrelated residuals and control of seasonality. The switching model estimated a 5°C increase in mean temperature and 10 mm precipitation were associated with increases in salmonellosis cases of 45.4% (95% CrI 40.4%, 50.5%) and 24.1% (95% CrI 17.0%, 31.6%), respectively. Conclusions Switching models improve on traditional time series models in quantifying weather–salmonellosis associations. A better understanding of how temperature and precipitation influence salmonellosis may identify where interventions can be made to lower the health and economic costs of salmonellosis.

Computational methods for the prediction of the structure and interactions of coiled-coil peptides

The past several years have seen significant advances in the development of computational methods for the prediction of the structure and interactions of coiled-coil peptides. These methods are generally based on pairwise correlations of amino acids, helical propensity, thermal melts and the energetics of sidechain interactions, as well as statistical patterns based on Hidden Markov Model (HMM) and Support Vector Machine (SVM) techniques. These methods are complemented by a number of public databases that contain sequences, motifs, domains and other details of coiled-coil structures identified by various algorithms. Some of these computational methods have been developed to make predictions of coiled-coil structure on the basis of sequence information; however, structural predictions of the oligomerisation state of these peptides still remains largely an open question due to the dynamic behaviour of these molecules. This review focuses on existing in silico methods for the prediction of coiled-coil peptides of functional importance using sequence and/or three-dimensional structural data.

The role of 25-hydroxyvitamin D deficiency in promoting insulin resistance and inflammation in patients with chronic kidney disease: A randomised controlled trial

BACKGROUND Approximately 50% of patients with stage 3 Chronic Kidney Disease are 25-hydroxyvitamin D insufficient, and this prevalence increases with falling glomerular filtration rate. Vitamin D is now recognised as having pleiotropic roles beyond bone and mineral homeostasis, with the vitamin D receptor and metabolising machinery identified in multiple tissues. Worryingly, recent observational data has highlighted an association between hypovitaminosis D and increased cardiovascular mortality, possibly mediated via vitamin D effects on insulin resistance and inflammation. The main hypothesis of this study is that oral Vitamin D supplementation will ameliorate insulin resistance in patients with Chronic Kidney Disease stage 3 when compared to placebo. Secondary hypotheses will test whether this is associated with decreased inflammation and bone/adipocyte-endocrine dysregulation. METHODS/DESIGN This study is a single-centre, double-blinded, randomised, placebo-controlled trial. Inclusion criteria include; estimated glomerular filtration rate 30-59 ml/min/1.73 m(2); aged >or=18 on entry to study; and serum 25-hydroxyvitamin D levels <75 nmol/L. Patients will be randomised 1:1 to receive either oral cholecalciferol 2000IU/day or placebo for 6 months. The primary outcome will be an improvement in insulin sensitivity, measured by hyperinsulinaemic euglycaemic clamp. Secondary outcome measures will include serum parathyroid hormone, cytokines (Interleukin-1beta, Interleukin-6, Tumour Necrosis Factor alpha), adiponectin (total and High Molecular Weight), osteocalcin (carboxylated and under-carboxylated), peripheral blood mononuclear cell Nuclear Factor Kappa-B p65 binding activity, brachial artery reactivity, aortic pulse wave velocity and waveform analysis, and indirect calorimetry. All outcome measures will be performed at baseline and end of study. DISCUSSION To date, no randomised controlled trial has been performed in pre-dialysis CKD patients to study the correlation between vitamin D status with supplementation, insulin resistance and markers of adverse cardiovascular risk. We remain hopeful that cholecalciferol may be a safe intervention, with health benefits beyond those related to bone-mineral homeostasis. TRIAL REGISTRATION Australian and New Zealand Clinical Trials Registry ACTRN12609000246280.

The tired foot. The effects of physical activity, energy expenditure and sleep on the diabetic foot population

Background The most common pathway to development of diabetes foot ulcers is repetitive daily activity stress on the plantar surface of the neuropathic foot. Studies suggest an association between different diabetic foot complications and physical activity. However, to the best of the authors knowledge the steps/day and sleep patterns of people with diabetic foot ulcers has yet to be investigated. This observational study aims to investigate the physical activity and sleep patterns of three groups of adults with type 2 diabetes and different foot complications Methods Participants with type 2 diabetes were recruited into three groups: 1. those with no reported foot complications (DNIL), 2. those with diagnosis of neuropathy (DPN) and 3. those with a neuropathic ulcer (DFU). Exclusion criteria included peripheral arterial disease and mobility aid use. Participants wore a SenseWear Pro 3 Armband continuously for 7 days and completed an Epworth Sleepiness Scale. The Armband is a validated automated measure of activity (walking steps, average Metabolic Equivalent Task (MET), physical activity (>3 METs) duration), energy expenditure(kJ) (total and physical activity (>3 METs)) and sleep (duration). Data on age, sex, BMI, diabetes duration and HbA1c were also collected. Results Sixty-Six (14 DNIL, 22 DPN and 30 DFU's participants were recruited; 71% males, mean age 61(±12) years, diabetes duration 13(±9) years, HbA1c 8.3(±2.8), BMI 32.6(±5.9), average METs 1.2(0.2). Significant differences were reported in mean(SD) steps/day (5,859(±2,381) in DNIL; 5,007(±3,349) in DPN and 3,271(±2,417) in DFU's and daily energy expenditure (10,868(±1,307)kJ in DNIL; 11,060(±1,916)kJ in DPN and 13,006(± 3,559) in DFU's(p <0.05). No significant differences were reported for average METs, physical activity duration or energy expenditure, sleep time or Epworth score (p>0.1). Conclusions Preliminary findings suggest people with diabetes are sedentary. Results indicate that patients with a diabetic foot ulcer work significantly less than those with neuropathy or nil complications and use significantly more energy to do so. Sleep Parameters showed no differences. Recruitment is still on going.