Rationale and design of the intravenous iron for treatment of anemia before cardiac surgery trial.

Background Approximately 20% to 30% of patients awaiting cardiac surgery are anemic. Anemia increases the likelihood of requiring a red cell transfusion and is associated with increased complications, intensive care, and hospital stay following surgery. Iron deficiency is the commonest cause of anemia and preoperative intravenous (IV) iron therapy thus may improve anemia and therefore patient outcome following cardiac surgery. We have initiated the intravenous iron for treatment of anemia before cardiac surgery (ITACS) Trial to test the hypothesis that in patients with anemia awaiting elective cardiac surgery, IV iron will reduce complications, and facilitate recovery after surgery. Methods ITACS is a 1,000 patient, international randomized trial in patients with anemia undergoing elective cardiac surgery. The patients, health care providers, data collectors, and statistician are blinded to whether patients receive IV iron 1,000 mg, or placebo, at 1-26 weeks before their planned date of surgery. The primary endpoint is the number of days alive and at home up to 90 days after surgery. Results To date, ITACS has enrolled 615 patients in 30 hospitals in 9 countries. Patient mean (SD) age is 66 (12) years, 63% are male, with a mean (SD) hemoglobin at baseline of 118 (12) g/L; 40% have evidence (ferritin <100 ng/mL and/or transferrin saturation <25%) suggestive of iron deficiency. Most (59%) patients have undergone coronary artery surgery with or without valve surgery. Conclusions The ITACS Trial will be the largest study yet conducted to ascertain the benefits and risks of IV iron administration in anemic patients awaiting cardiac surgery.

Healthcare Funding Decisions and Real-World Benefits: Reducing Bias by Matching Untreated Patients.

Governments and health insurers often make funding decisions based on health gains from randomised controlled trials. These decisions are inherently uncertain because health gains in trials may not translate to practice owing to differences in the population, treatment use and setting. Post-market analysis of real-world data can provide additional evidence but estimates from standard matching methods may be biased when unobserved characteristics explain whether a patient is treated and their outcomes. We propose a new untreated matching approach that can reduce this bias. Our approach utilises the outcomes of contemporaneous untreated patients to improve the matching of treated and historical control patients. We assess the performance of this new approach compared to standard matching using a simulation study and demonstrate the steps required using a funding decision for prostate cancer treatments in Australia. Our simulation study shows that our new matching approach eliminates nearly all bias when unobserved treatment selection is related to outcomes, and outperforms standard matching in most scenarios. In our empirical example, standard matching overestimated survival by 15% (95% confidence interval 2-34) compared to our untreated matching approach. The health gains estimated using our approach were slightly lower than expected based on the trial evidence, but we also found evidence that in practice prescribers ceased prior therapies earlier, treated a more vulnerable population and continued treatment for longer. Our untreated matching approach offers researchers a new tool for reducing uncertainty in healthcare funding decisions using real-world data.

Revealed and Stated Preferences of Decision Makers for Priority Setting in Health Technology Assessment: A Systematic Review.

BACKGROUND: There is much interest from stakeholders in understanding how health technology assessment (HTA) committees make national funding decisions for health technologies. A growing literature has analysed past decisions by committees (revealed preference, RP studies) and hypothetical decisions by committee members (stated preference, SP studies) to identify factors influencing decisions and assess their importance. OBJECTIVES: A systematic review of the literature was undertaken to provide insight into committee preferences for these factors (after controlling for other factors) and the methods used to elicit them. METHODS: Ovid Medline, Embase, Econlit and Web of Science were searched from inception to 11 May 2017. Included studies had to have investigated factors considered by HTA committees and to have conducted multivariate analysis to identify the effect of each factor on funding decisions. Factors were classified as being important based on statistical significance, and their impact on decisions was compared using marginal effects. RESULTS: Twenty-three RP and four SP studies (containing 42 analyses) of 14 HTA committees met the inclusion criteria. Although factors were defined differently, the SP literature generally found clinical efficacy, cost-effectiveness and equity factors (such as disease severity) were each important to the Pharmaceutical Benefits Advisory Committee (PBAC), the National Institute for Health and Care Excellence (NICE) and the All Wales Medicines Strategy Group. These findings were supported by the RP studies of the PBAC, but not the other committees, which found funding decisions by these and other committees were mostly influenced by the acceptance of the clinical evidence and, where applicable, cost-effectiveness. Trust in the evidence was very important for decision makers, equivalent to reducing the incremental cost-effectiveness ratio (cost per quality-adjusted life-year) by A$38,000 (Australian dollars) for the PBAC and £15,000 for NICE. CONCLUSIONS: This review found trust in the clinical evidence and, where applicable, cost-effectiveness were important for decision makers. Many methodological differences likely contributed to the diversity in some of the other findings across studies of the same committee. Further work is needed to better understand how competing factors are valued by different HTA committees.

6-PACK programme to decrease fall injuries in acute hospitals: cluster randomised controlled trial.

OBJECTIVE: To evaluate the effect of the 6-PACK programme on falls and fall injuries in acute wards. DESIGN: Cluster randomised controlled trial. SETTING: Six Australian hospitals. PARTICIPANTS: All patients admitted to 24 acute wards during the trial period. INTERVENTIONS: Participating wards were randomly assigned to receive either the nurse led 6-PACK programme or usual care over 12 months. The 6-PACK programme included a fall risk tool and individualised use of one or more of six interventions: "falls alert" sign, supervision of patients in the bathroom, ensuring patients' walking aids are within reach, a toileting regimen, use of a low-low bed, and use of a bed/chair alarm. MAIN OUTCOME MEASURES: The co-primary outcomes were falls and fall injuries per 1000 occupied bed days. RESULTS: During the trial, 46 245 admissions to 16 medical and eight surgical wards occurred. As many people were admitted more than once, this represented 31 411 individual patients. Patients' characteristics and length of stay were similar for intervention and control wards. Use of 6-PACK programme components was higher on intervention wards than on control wards (incidence rate ratio 3.05, 95% confidence interval 2.14 to 4.34; P<0.001). In all, 1831 falls and 613 fall injuries occurred, and the rates of falls (incidence rate ratio 1.04, 0.78 to 1.37; P=0.796) and fall injuries (0.96, 0.72 to 1.27; P=0.766) were similar in intervention and control wards. CONCLUSIONS: Positive changes in falls prevention practice occurred following the introduction of the 6-PACK programme. However, no difference was seen in falls or fall injuries between groups. High quality evidence showing the effectiveness of falls prevention interventions in acute wards remains absent. Novel solutions to the problem of in-hospital falls are urgently needed. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12611000332921.

The extra resource burden of in-hospital falls: a cost of falls study.

OBJECTIVE: To quantify the additional hospital length of stay (LOS) and costs associated with in-hospital falls and fall injuries in acute hospitals in Australia. DESIGN, SETTING AND PARTICIPANTS: A multisite prospective cohort study conducted during 2011-2013 in the control wards of a falls prevention trial (6-PACK). The trial included all admissions to 12 acute medical and surgical wards of six Australian hospitals. In-hospital falls data were collected from medical record reviews, daily verbal reports by ward nurse unit managers, and hospital incident reporting and administrative databases. Clinical costing data were linked for three of the six participating hospitals to calculate patient-level costs. OUTCOME MEASURES: Hospital LOS and costs associated with in-hospital falls and fall injuries for each patient admission. RESULTS: We found that 966 of a total of 27 026 hospital admissions (3.6%) involved at least one fall, and 313 (1.2%) at least one fall injury, a total of 1330 falls and 418 fall injuries. After adjustment for age, sex, cognitive impairment, admission type, comorbidity and clustering by hospital, patients who had an in-hospital fall had a mean increase in LOS of 8 days (95% CI, 5.8-10.4; P < 0.001) compared with non-fallers, and incurred mean additional hospital costs of $6669 (95% CI, $3888-$9450; P < 0.001). Patients with a fall-related injury had a mean increase in LOS of 4 days (95% CI, 1.8-6.6; P = 0.001) compared with those who fell without injury, and there was also a tendency to additional hospital costs (mean, $4727; 95% CI, -$568 to $10 022; P = 0.080). CONCLUSION: Patients who experience an in-hospital fall have significantly longer hospital stays and higher costs. Programs need to target the prevention of all falls, not just the reduction of fall-related injuries.

Preferences for oral anticoagulants in atrial fibrillation: a best-best discrete choice experiment.

BACKGROUND: Atrial fibrillation (AF) is recognised as a growing clinical and public health problem in many countries, owing to disability and death from stroke associated with the condition, high hospitalisation costs and an increasing prevalence with ageing populations. Under-treatment with oral anticoagulants has been a significant challenge of treatment, historically related to patient concerns over the safety and convenience of warfarin, which until recently was the only oral anticoagulant available. OBJECTIVES: The aim of this study is to examine: (1) patient preferences for attributes of warfarin and the new oral anticoagulants (dabigatran, rivaroxaban, apixaban) in AF; (2) which attributes are most important; and (3) whether current under-treatment is likely to improve with the new oral anticoagulants. METHODS: This study was conducted in Melbourne, Australia, with members of the general public with or without AF aged ≥40 years, where those without AF proxy for newly-diagnosed patients. Participants completed a computerised best-best discrete choice experiment (and follow-up interview) as if they had AF with a moderate-to-high risk of stroke. Choice data were modelled using mixed rank-ordered logit. Relative value was explored via estimation of marginal rates of substitution with predicted probability analysis used to simulate potential uptake of oral anticoagulants. RESULTS: Seventy-six participants were recruited and completed the study. Efficacy (stroke risk) was more important than safety (bleed risk, antidote), which were both considerably more important than convenience factors (blood tests, dose frequency, drug or food interactions). Cost was also important. Predicted use of the new oral anticoagulants (and under-treatment of AF) using simulation, given moderate-to-high risk of stroke, is 25 % (52 %), 54 % (29 %) and 70 % (21 %) assuming a market price of AUD$120/month, AUD$30/month (subsidised price) and AUD$30/month with an antidote, respectively. CONCLUSIONS: Based on the study sample and the modelled attributes, the overall profiles of the new oral anticoagulants were preferred to warfarin as their cost decreased. Public subsidisation and the development of antidotes (such as vitamin K for warfarin) for the new oral anticoagulants may have a positive effect on the under-treatment of AF.

Evaluating the impact of depression, anxiety & autonomic function on health related quality of life, vocational functioning and health care utilisation in acute coronary syndrome patients: the ADVENT study protocol.

BACKGROUND: Depression and anxiety are highly prevalent and co-morbid in acute coronary syndrome patients. Somatic and cognitive subtypes of depression and anxiety in acute coronary syndrome have been shown to be associated with mortality although their association with patient outcomes is unknown, as are the mechanisms that underpin these associations. We are conducting a prospective cohort study which aims to examine in acute coronary syndrome patients: (1) the role of somatic subtypes of depression and anxiety as predictors of health related quality of life outcomes; (2) how somatic subtypes of depression and anxiety relate to long term vocational functioning and healthcare utilisation; and (3) the role of the autonomic nervous system assessed by heart rate variability as a moderator of these associations. METHODS: Patients are being screened after index admission for acute coronary syndrome at a single, high volume centre, MonashHeart, Monash Health, Victoria, Australia. The inclusion criterion is all patients aged > 21 years old and fluent in English admitted to MonashHeart, Monash Health with a diagnosis of acute coronary syndrome. The primary outcome is mean health related quality of life (Short Form-36) Physical and Mental Health Summary scores at 12 and 24 months in subtypes with somatic symptoms of depression and anxiety. Depressive domains are assessed by the Beck Depression Inventory II and the Cardiac Depression Scale. Anxiety is measured using the Speilberger State-Trait Anxiety Inventory and the Crown Crisp Phobic Anxiety questionnaire. Secondary outcomes include clinical variables, healthcare service utilisation and vocational functioning. DISCUSSION: This manuscript presents the protocol for a prospective cohort study which will investigate the role of somatic subtypes of depression and anxiety as predictors of health related quality of life, long-term vocational functioning and health service use, and the role of the autonomic nervous system in moderating these associations. Findings from the study have the potential to inform more effective pharmacological, psychological and behavioural interventions and better guide health policy on the use of health care resources.

In-hospital falls and fall-related injuries: a protocol for a cost of fall study.

BACKGROUND: In-hospital falls are common and pose significant economic burden on the healthcare system. To date, few studies have quantified the additional cost of hospitalisation associated with an in-hospital fall or fall-related injury. The aim of this study is to determine the additional length of stay and hospitalisation costs associated with in-hospital falls and fall-related injuries, from the acute hospital perspective. METHODS AND DESIGN: A multisite prospective study will be conducted as part of a larger falls-prevention clinical trial-the 6-PACK project. This study will involve 12 acute medical and surgical wards from six hospitals across Australia. Patient and admission characteristics, outcome and hospitalisation cost data will be prospectively collected on approximately 15 000 patients during the 15-month study period. A review of all in-hospital fall events will be conducted using a multimodal method (medical record review and daily verbal report from the nurse unit manager, triangulated with falls recorded in the hospital incident reporting and administrative database), to ensure complete case ascertainment. Hospital clinical costing data will be used to calculate patient-level hospitalisation costs incurred by a patient during their inpatient stay. Additional hospital and hospital resource utilisation costs attributable to in-hospital falls and fall-related injuries will be calculated using linear regression modelling, adjusting for a priori-defined potential confounding factors. DISCUSSION: This protocol provides the detailed statement of the planned analysis. The results from this study will be used to support healthcare planning, policy making and allocation of funding relating to falls prevention within acute hospitals.

The 6-PACK programme to decrease falls and fall-related injuries in acute hospitals: protocol for an economic evaluation alongside a cluster randomised controlled trial.

BACKGROUND: Falls are a common hospital occurrence complicating the care of patients. From an economic perspective, the impact of in-hospital falls and related injuries is substantial. However, few studies have examined the economic implications of falls prevention interventions in an acute care setting. The 6-PACK programme is a targeted nurse delivered falls prevention programme designed specifically for acute hospital wards. It includes a risk assessment tool and six simple strategies that nurses apply to patients classified as high-risk by the tool. OBJECTIVE: To examine the incremental cost-effectiveness of the 6-PACK programme for the prevention of falls and fall-related injuries, compared with usual care practice, from an acute hospital perspective. METHODS AND DESIGN: The 6-PACK project is a multicentre cluster randomised controlled trial (RCT) that includes 24 acute medical and surgical wards from six hospitals in Australia to investigate the efficacy of the 6-PACK programme. This economic evaluation will be conducted alongside the 6-PACK cluster RCT. Outcome and hospitalisation cost data will be prospectively collected on approximately 16,000 patients admitted to the participating wards during the 12-month trial period. The results of the economic evaluation will be expressed as 'cost or saving per fall prevented' and 'cost or saving per fall-related injury prevented' calculated from differences in mean costs and effects in the intervention and control groups, to generate an incremental cost-effectiveness ratio (ICER). DISCUSSION: This economic evaluation will provide an opportunity to explore the cost-effectiveness of a targeted nurse delivered falls prevention programme for reducing in-hospital falls and fall-related injuries. This protocol provides a detailed statement of a planned economic evaluation conducted alongside a cluster RCT to investigate the efficacy of the 6-PACK programme to prevent falls and fall-related injuries. TRIAL REGISTRATION NUMBER: The protocol for the cluster RCT is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12611000332921).

The 6-PACK programme to decrease fall-related injuries in acute hospitals: protocol for a cluster randomised controlled trial.

BACKGROUND AND AIMS: In-hospital fall-related injuries are a source of personal harm, preventable hospitalisation costs, and access block through increased length of stay. Despite increased fall prevention awareness and activity over the last decade, rates of reported fall-related fractures in hospitals appear not to have decreased. This cluster randomised controlled trial (RCT) aims to determine the efficacy of the 6-PACK programme for preventing fall-related injuries, and its generalisability to other acute hospitals. METHODS: 24 acute medical and surgical wards from six to eight hospitals throughout Australia will be recruited for the study. Wards will be matched by type and fall-related injury rates, then randomly allocated to the 6-PACK intervention (12 wards) or usual care control group (12 wards). The 6-PACK programme includes a nine-item fall risk assessment and six nursing interventions: 'falls alert' sign; supervision of patients in the bathroom; ensuring patient's walking aids are within reach; establishment of a toileting regime; use of a low-low bed; and use of bed/chair alarm. Intervention wards will be supported by a structured implementation strategy. The primary outcomes are fall and fall-related injury rates 12 months following 6-PACK implementation. DISCUSSION: This study will involve approximately 16,000 patients, and as such is planned to be the largest hospital fall prevention RCT to be undertaken and the first to be powered for the important outcome of fall-related injuries. If effective, there is potential to implement the programme widely as part of daily patient care in acute hospital wards where fall-related injuries are a problem.

Elf5 is essential for early embryogenesis and mammary gland development during pregnancy and lactation.

Elf5 is an epithelial-specific ETS factor. Embryos with a null mutation in the Elf5 gene died before embryonic day 7.5, indicating that Elf5 is essential during mouse embryogenesis. Elf5 is also required for proliferation and differentiation of mouse mammary alveolar epithelial cells during pregnancy and lactation. The loss of one functional allele led to complete developmental arrest of the mammary gland in pregnant Elf5 heterozygous mice. A quantitative mRNA expression study and Western blot analysis revealed that decreased expression of Elf5 correlated with the downregulation of milk proteins in Elf5(+/-) mammary glands. Mammary gland transplants into Rag(-/-) mice demonstrated that Elf5(+/-) mammary alveolar buds failed to develop in an Elf5(+/+) mammary fat pad during pregnancy, demonstrating an epithelial cell autonomous defect. Elf5 expression was reduced in Prolactin receptor (Prlr) heterozygous mammary glands, which phenocopy Elf5(+/-) glands, suggesting that Elf5 and Prlr are in the same pathway. Our data demonstrate that Elf5 is essential for developmental processes in the embryo and in the mammary gland during pregnancy.

Evaluating heterogeneity in cumulative meta-analyses.

BACKGROUND: Recently developed measures such as I2 and H allow the evaluation of the impact of heterogeneity in conventional meta-analyses. There has been no examination of the development of heterogeneity in the context of a cumulative meta-analysis. METHODS: Cumulative meta-analyses of five smoking cessation interventions (clonidine, nicotine replacement therapy using gum and patch, physician advice and acupuncture) were used to calculate I2 and H. These values were plotted by year of publication, control event rate and sample size to trace the development of heterogeneity over these covariates. RESULTS: The cumulative evaluation of heterogeneity varied according to the measure of heterogeneity used and the basis of cumulation. Plots produced from the calculations revealed areas of heterogeneity useful in the consideration of potential sources for further study. CONCLUSION: The examination of heterogeneity in conjunction with summary effect estimates in a cumulative meta-analysis offered valuable insight into the evolution of variation. Such information is not available in the context of conventional meta-analysis and has the potential to lead to the development of a richer picture of the effectiveness of interventions.