Comparison of treatment effect sizes associated with surrogate and final patient relevant outcomes in randomised controlled trials: meta-epidemiological study

Objective To quantify and compare the treatment effect and risk of bias of trials reporting biomarkers or intermediate outcomes (surrogate outcomes) versus trials using final patient relevant primary outcomes. Design Meta-epidemiological study. Data sources All randomised clinical trials published in 2005 and 2006 in six high impact medical journals: Annals of Internal Medicine, BMJ, Journal of the American Medical Association, Lancet, New England Journal of Medicine, and PLoS Medicine. Study selection Two independent reviewers selected trials. Data extraction Trial characteristics, risk of bias, and outcomes were recorded according to a predefined form. Two reviewers independently checked data extraction. The ratio of odds ratios was used to quantify the degree of difference in treatment effects between the trials using surrogate outcomes and those using patient relevant outcomes, also adjusted for trial characteristics. A ratio of odds ratios >1.0 implies that trials with surrogate outcomes report larger intervention effects than trials with patient relevant outcomes. Results 84 trials using surrogate outcomes and 101 using patient relevant outcomes were considered for analyses. Study characteristics of trials using surrogate outcomes and those using patient relevant outcomes were well balanced, except for median sample size (371 v 741) and single centre status (23% v 9%). Their risk of bias did not differ. Primary analysis showed trials reporting surrogate endpoints to have larger treatment effects (odds ratio 0.51, 95% confidence interval 0.42 to 0.60) than trials reporting patient relevant outcomes (0.76, 0.70 to 0.82), with an unadjusted ratio of odds ratios of 1.47 (1.07 to 2.01) and adjusted ratio of odds ratios of 1.46 (1.05 to 2.04). This result was consistent across sensitivity and secondary analyses. Conclusions Trials reporting surrogate primary outcomes are more likely to report larger treatment effects than trials reporting final patient relevant primary outcomes. This finding was not explained by differences in the risk of bias or characteristics of the two groups of trials.

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.

Modelling end-of-life care practices: Factors associated with critical care nurse engagement in care provision

Objective To identify factors associated with critical care nurses’ engagement in end-of-life care practices. Methods Multivariable regression modelling was undertaken on 392 responses to an online self-report survey of end-of-life care practices and factors influencing practice by Australian critical care nurses’. Univariate general linear models were built for six end-of-life care practice areas. Results Six statistically significant (p < 0.001) models were developed: Information sharing F(3, 377) = 40.53, adjusted R2 23.8%; Environmental modification F(5, 380) = 19.55, adjusted R2 19.4%; Emotional support F(10, 366) = 12.10, adjusted R2 22.8%; Patient and family centred decision making F(8, 362) = 17.61 adjusted R2 26.4%; Symptom management F(8, 376) = 7.10, adjusted R2 11.3%; and Spiritual support F(9, 367) = 14.66, adjusted R2 24.6%. Stronger agreement with values consistent with a palliative approach, and greater support for patient and family preferences were associated with higher levels of engagement in end-of-life care practices. Higher levels of preparedness and access to opportunities for knowledge acquisition were associated with engagement in the interpersonal practices of patient and family centred decision making and emotional support. Conclusion This study provides evidence for interventions to address factors associated with nurse engagement to increase participation in all end-of-life care practice areas.

David Jones seeks to exploit top end gap in Australian grocery

While Australia’s supermarkets continue to battle on price, the South African owner of David Jones, Woolworths Holdings, has found a gap in the Australian grocery market and is preparing to exploit it. Reports that the group has appointed Pieter de Wet to overhaul the David Jones food business signals once again the ever-changing face of the Australian food and grocery landscape. A re-energised David Jones food offer will provide positive outcomes for both shoppers and suppliers, while potentially becoming another headache for Coles and Woolworths.

Should I stay or should I go?: Rural and remote students in first year university stem courses

Research on the achievement of rural and remote students in science and mathematics is located within a context of falling levels of participation in physical science and mathematics courses in Australian schools, and underrepresentation of rural students in higher education. International studies such as the Programme of International Student Assessment (PISA), have reported lower levels of mathematical and scientific literacy in Australian students from rural and remote schools (Thomson et al, 2011). The SiMERR national survey of science, mathematics and ICT education in rural and regional Australia (Lyons et al, 2006) identified factors affecting student achievement in rural and remote schools. Many of the issues faced by rural and remote students in their schools are likely to have implications on their university enrolments in science, technology, engineering and mathematics (STEM) courses. For example, rural and remote students are less likely to attend university in general than their city counterparts and higher university attrition rates have been reported for remote students nationally. This paper examines the responses of a sample of rural/remote Australian first year STEM students at Australian universities to two questions. These related to their intentions to complete the course; and whether -and if so, why- they had ever considered withdrawing from their course. Results indicated that rural students who were still in their course by the end of first year were no more or less likely to consider withdrawing than were their peers from more populous centres. However, almost 20% of the rural cohort had considered withdrawing at some stage in their course, and their explanations provide insights into the reasoning of those who may not persist with their courses at university. These results, in the context of the greater attrition rate of remote students from university, point to the need to identify factors that positively impact on rural and remote students’ interest and achievement in science and mathematics. It also highlights a need for future research into the particular issues remote students may face in deciding whether or not to do science at the two key transition points of senior school and university/TAFE studies, and whether or not to persist in their tertiary studies. This paper is positioned at the intersection of two problems in Australian education. The first is a context of falling levels of participation in physical science and mathematics courses in Australian universities. The second is persistent inequitable access to, and retention in, tertiary education for students from rural and remote areas. Despite considerable research attention to both of these areas over recent years these problems have thus far proved to be intractable. This paper therefore aims to briefly review the relevant Australian literature pertaining to these issues; that is, declining STEM enrolments, and the underrepresentation and retention of rural/remote students in higher education. Given the related problems in these two overlapping domains, we then explore the views of first year rural students enrolled in courses, in relation to their intentions of withdrawing (or not) and the associated reasons for their views.

End-of-life care pathways for improving outcomes in caring for the dying

This is an updated version of a Cochrane review published in Issue 11, 2013 in the Cochrane Library. In many clinical areas, integrated care pathways are utilised as structured multidisciplinary care plans that detail essential steps in caring for patients with specific clinical problems. In particular, care pathways for the dying have been developed as a model to improve care of patients who are in the last days of life. The care pathways were designed with an aim of ensuring that the most appropriate management occurs at the most appropriate time, and that it is provided by the most appropriate health professional. Since the last update, there have been sustained concerns about the safety of implementing end-of-life care pathways, particularly in the United Kingdom (UK). Therefore, there is a significant need for clinicians and policy makers to be informed about the effects of end-of-life care pathways via a systematic review.

The effect of flexor tenotomy on healing and prevention of neuropathic diabetic foot ulcers on the distal end of the toe

Background Flexor tenotomy is a minimally invasive surgical alternative for the treatment of neuropathic diabetic foot ulcers on the distal end of the toe. The influence of infection on healing and time to heal after flexor tenotomy is unknown. Flexor tenotomy can also be used as a prophylactic treatment. The effectiveness as a prophylactic treatment has not been described before. Methods A retrospective study was performed with the inclusion of all consecutive flexor tenotomies from one hospital between January 2005 and December 2011. Results From 38 ulcers, 35 healed (92%), with a mean time to heal of 22 ± 26 days. The longest duration for healing was found for infected ulcers that were penetrating to bone (35 days; p = .042). Cases of prophylactic flexor tenotomies (n=9) did not result in any ulcer or other complications during follow-up. Conclusions The results of this study suggest that flexor tenotomy may be beneficial for neuropathic diabetic foot ulcers on the distal end of the toe, with a high healing percentage and a short mean time to heal. Infected ulcers that penetrated to bone took a significantly longer time to heal. Prospective research, to confirm the results of this retrospective study, should be performed.

Guest editorial: End of life law, ethics, policy and practice

The International Conference on End of Life: Law, Ethics, Policy and Practice was held at Queensland University of Technology, Brisbane, Australia in August 2014. It was co-hosted by the Australian Centre for Health Law Research, the Dalhousie Health Law Institute (Canada) and the Tsinghua Health Law Research Center (China). The conference attracted almost 350 delegates from 26 countries and included representation from over a dozen different disciplines with an interest in end of life care.

The assessment of ecological condition in south-east Queensland, Australia: An evaluation of reliability across variable environments and surrogate efficacy for biodiversity values

Multimetric ecological condition assessment has become an important biodiversity management tool. This study was the first to examine the reliability of these ecological surrogates across variable environments, and the implications for surrogate efficacy. It was demonstrated that through strategic application and design of the multimetric ecological condition index, the effects of environmental gradients and disturbance regimes can be mitigated, and that ecological condition assessment may serve as a scientifically rigorous approach for conservation planning.

Fast forward to the end: Stories of the cassette magazine

Although they made up a significant share of the retail music market from the 60s to the 90s, and were often used as promotional and marketing tools, cassettes became re-configured in the 80s as an integral component of cassette magazines. Binding sound, music, talk, text, visual art and design, they were a truly innovative interdisciplinary form. This paper explores the history of these artefacts with particular emphasis on the Brisbane underground music scene of the late 70s and 80s, and discusses their significance in as a bridge between the music scene and art scenes of this period.

Too ill to will? deathbed wills: assessing testamentary capacity near the end of life

Assessing testamentary capacity in the terminal phase of an illness or at a person's deathbed is fraught with challenges for both doctors and lawyers. Numerous issues need to be considered when assessing capacity for a will. These issues are exacerbated when such an assessment needs to be undertaken at the bedside of a dying patient. The nature and severity of the illness, effects on cognition of the terminal illness, effects of medication, urgency, psychological and emotional factors, interactions with carers, family and lawyers, and a range of other issues confound and complicate the assessment of capacity. What is the doctor's role in properly assessing capacity in this context and how does this role intersect with the legal issues? Doctors will play an increasing role in assessing testamentary capacity in this setting. The ageing of society, more effective treatment of acute illness and, often, the prolongation of dying are only some of the factors leading to this increasing need. However, despite its importance and increasing prevalence, the literature addressing this challenging practical area is scarce and offers limited guidance. This paper examines these challenges and discusses some practical approaches.

Futility and the law: Knowledge, practice and attitudes of doctors in end of life care

Despite the potential harm to patients (and others) and the financial cost of providing futile treatment at the end of life, this practice occurs. This article reports on empirical research undertaken in Queensland that explores doctors’ perceptions about the law that governs futile treatment at the end of life, and the role it plays in medical practice. The findings reveal that doctors have poor knowledge of their legal obligations and powers when making decisions about withholding or withdrawing futile treatment at the end of life; their attitudes towards the law were largely negative; and the law affected their clinical practice and had or would cause them to provide futile treatment.