Using discrete-choice experiments to elicit preferences for digital wearable health technology for self-management of chronic kidney disease.

OBJECTIVES: Wearable digital health technologies (DHTs) have the potential to improve chronic kidney disease (CKD) management through patient engagement. This study aimed to investigate and elicit preferences of individuals with CKD toward wearable DHTs designed to support self-management of their condition. METHODS: Using the results of our review of the published literature and after conducting qualitative patient interviews, five-choice attributes were identified and included in a discrete-choice experiment. The design consisted of 10-choice tasks, each comprising two hypothetical technologies and one opt-out scenario. We collected data from 113 adult patients with CKD stages 3-5 not on dialysis and analyzed their responses via a latent class model to explore preference heterogeneity. RESULTS: Two patient segments were identified. In all preference segments, the most important attributes were the device appearance, format, and type of information provided. Patients within the largest preference class (70 percent) favored information provided in any format except the audio, while individuals in the other class preferred information in text format. In terms of the style of engagement with the device, both classes wanted a device that provides options rather than telling them what to do. CONCLUSIONS: Our analysis indicates that user preferences differ between patient subgroups, supporting the case for offering a different design of the device for different patients' strata, thus moving away from a one-size-fits-all service provision. Furthermore, we showed how to leverage the information from user preferences early in the R&D process to inform and support the provision of nuanced person-centered wearable DHTs.

A bias-adjusted evidence synthesis of RCT and observational data: the case of total hip replacement.

Evaluation of clinical effectiveness of medical devices differs in some aspects from the evaluation of pharmaceuticals. One of the main challenges identified is lack of robust evidence and a will to make use of experimental and observational studies (OSs) in quantitative evidence synthesis accounting for internal and external biases. Using a case study of total hip replacement to compare the risk of revision of cemented and uncemented implant fixation modalities, we pooled treatment effect estimates from OS and RCTs, and simplified existing methods for bias-adjusted evidence synthesis to enhance practical application. We performed an elicitation exercise using methodological and clinical experts to determine the strength of beliefs about the magnitude of internal and external bias affecting estimates of treatment effect. We incorporated the bias-adjusted treatment effects into a generalized evidence synthesis, calculating both frequentist and Bayesian statistical models. We estimated relative risks as summary effect estimates with 95% confidence/credibility intervals to capture uncertainty. When we compared alternative approaches to synthesizing evidence, we found that the pooled effect size strongly depended on the inclusion of observational data as well as on the use bias-adjusted estimates. We demonstrated the feasibility of using observational studies in meta-analyses to complement RCTs and incorporate evidence from a wider spectrum of clinically relevant studies and healthcare settings. To ensure internal validity, OS data require sufficient correction for confounding and selection bias, either through study design and primary analysis, or by applying post-hoc bias adjustments to the results. © 2017 The Authors. Health Economics published by John Wiley & Sons, Ltd.

Clinical and cost-effectiveness of compression hosiery versus compression bandages in treatment of venous leg ulcers (Venous leg Ulcer Study IV, VenUS IV): a randomised controlled trial.

BACKGROUND: Drawbacks exist with the standard treatment (four-layer compression bandages) for venous leg ulcers. We have therefore compared the clinical effectiveness and cost-effectiveness of two-layer compression hosiery with the four-layer bandage for the treatment of such ulcers. METHODS: We undertook this pragmatic, open, randomised controlled trial with two parallel groups in 34 centres in England and Northern Ireland. The centres were community nurse teams or services, family doctor practices, leg ulcer clinics, tissue viability clinics or services, and wound clinics. Participants were aged 18 years or older with a venous leg ulcer and an ankle brachial pressure index of at least 0·8, and were tolerant of high compression. We randomly allocated participants (1:1) to receive two-layer compression hosiery or a four-layer bandage, using a remote randomisation service and prevalidated computer randomisation program. Participants were stratified by ulcer duration and ulcer area with permuted blocks (block sizes four and six). The primary endpoint was time to ulcer healing, with a maximum follow-up of 12 months. Although participants and health-care providers were not masked to treatment allocation, the primary endpoint was measured by masked assessment of photographs. Primary analysis was intention to treat with Cox regression, with adjustment for ulcer area, ulcer duration, physical mobility, and centre. This trial is registered with the ISRCTN register, number ISRCTN49373072. FINDINGS: We randomly allocated 457 participants to the two treatment groups: 230 to two-layer hosiery and 227 to the four-layer bandage, of whom 453 (230 hosiery and 223 bandage) contributed data for analysis. Median time to ulcer healing was 99 days (95% CI 84-126) in the hosiery group and 98 days (85-112) in the bandage group, and the proportion of ulcers healing was much the same in the two groups (70·9% hosiery and 70·4% bandage). More hosiery participants changed their allocated treatment (38·3% hosiery vs 27·0% bandage; p=0·02). 300 participants had 895 adverse events, of which 85 (9·5%) were classed as serious but unrelated to trial treatment. INTERPRETATION: Two-layer compression hosiery is a viable alternative to the four-layer bandage-it is equally as effective at healing venous leg ulcers. However, a higher rate of treatment changes in participants in the hosiery group than in the bandage group suggests that hosiery might not be suitable for all patients. FUNDING: NIHR Health Technology Assessment programme (07/60/26).

A dose-effect network meta-analysis model with application in antidepressants using restricted cubic splines.

Network meta-analysis has been used to answer a range of clinical questions about the preferred intervention for a given condition. Although the effectiveness and safety of pharmacological agents depend on the dose administered, network meta-analysis applications typically ignore the role that drugs dosage plays in the results. This leads to more heterogeneity in the network. In this paper, we present a suite of network meta-analysis models that incorporate the dose-effect relationship using restricted cubic splines. We extend existing models into a dose-effect network meta-regression to account for study-level covariates and for groups of agents in a class-effect dose-effect network meta-analysis model. We apply our models to a network of aggregate data about the efficacy of 21 antidepressants and placebo for depression. We find that all antidepressants are more efficacious than placebo after a certain dose. Also, we identify the dose level at which each antidepressant's effect exceeds that of placebo and estimate the dose beyond which the effect of antidepressants no longer increases. When covariates were introduced to the model, we find that studies with small sample size tend to exaggerate antidepressants efficacy for several of the drugs. Our dose-effect network meta-analysis model with restricted cubic splines provides a flexible approach to modelling the dose-effect relationship in multiple interventions. Decision-makers can use our model to inform treatment choice.

Developing a model Fracture Liaison Service consultation with patients, carers and clinicians: a Delphi survey to inform content of the iFraP complex consultation intervention.

Fracture Liaison Services are recommended to deliver best practice in secondary fracture prevention. This modified Delphi survey, as part of the iFraP (Improving uptake of Fracture Prevention drug Treatments) study, provides consensus regarding tasks for clinicians in a model Fracture Liaison Service consultation. PURPOSE: The clinical consultation is of pivotal importance in addressing barriers to treatment adherence. The aim of this study was to agree to the content of the 'model Fracture Liaison Service (FLS) consultation' within the iFraP (Improving uptake of Fracture Prevention drug Treatments) study. METHODS: A Delphi survey was co-designed with patients and clinical stakeholders using an evidence synthesis of current guidelines and content from frameworks and theories of shared decision-making, communication and medicine adherence. Patients with osteoporosis and/or fragility fractures, their carers, FLS clinicians and osteoporosis specialists were sent three rounds of the Delphi survey. Participants were presented with potential consultation content and asked to rate their perception of the importance of each statement on a 5-point Likert scale and to suggest new statements (Round 1). Lowest rated statements were removed or amended after Rounds 1 and 2. In Round 3, participants were asked whether each statement was 'essential' and percentage agreement calculated; the study team subsequently determined the threshold for essential content. RESULTS: Seventy-two, 49 and 52 patients, carers and clinicians responded to Rounds 1, 2 and 3 respectively. One hundred twenty-two statements were considered. By Round 3, consensus was reached, with 81 statements deemed essential within FLS consultations, relating to greeting/introductions; gathering information; considering therapeutic options; eliciting patient perceptions; establishing shared decision-making preferences; sharing information about osteoporosis and treatments; checking understanding/summarising; and signposting next steps. CONCLUSIONS: This Delphi consensus exercise has summarised for the first time patient/carer and clinician consensus regarding clearly defined tasks for clinicians in a model FLS consultation.

Systematic Review of Health Economic Evaluation Studies Developed in Brazil from 1980 to 2013.

BACKGROUND: Brazil has sought to use economic evaluation to support healthcare decision-making processes. While a number of health economic evaluations (HEEs) have been conducted, no study has systematically reviewed the quality of Brazilian HEE. The objective of this systematic review was to provide an overview regarding the state of HEE research and to evaluate the number, characteristics, and quality of reporting of published HEE studies conducted in a Brazilian setting. METHODS: We systematically searched electronic databases (MEDLINE, EMBASE, Latin American, and Caribbean Literature on Health Sciences Database, Scientific Electronic Library Online, NHS Economic Evaluation Database, health technology assessment Database, Bireme, and Biblioteca Virtual em Saúde Economia da Saúde); citation indexes (SCOPUS, Web of Science), and Sistema de Informação da Rede Brasileira de Avaliação de Tecnologia em Saúde. Partial and full HEEs published between 1980 and 2013 that referred to a Brazilian setting were considered for inclusion. RESULTS: In total, 535 studies were included in the review, 36.8% of these were considered to be full HEE. The category of healthcare technologies more frequently assessed were procedures (34.8%) and drugs (28.8%) which main objective was treatment (72.1%). Forty-four percent of the studies reported their funding source and 36% reported a conflict of interest. Overall, the full HEE quality of reporting was satisfactory. But some items were generally poorly reported and significant improvement is required: (1) methods used to estimate healthcare resource use quantities and unit costs, (2) methods used to estimate utility values, (3) sources of funding, and (4) conflicts of interest. CONCLUSION: A steady number of HEE have been published in Brazil since 1980. To improve their contribution to inform national healthcare policy efforts need to be made to enhance the quality of reporting of HEEs and promote improvements in the way HEEs are designed, implemented (i.e., using sound methods for HEEs) and reported.

The cost effectiveness of bisphosphonates for the prevention and treatment of osteoporosis: a structured review of the literature.

Osteoporotic fragility fractures constitute a significant public health concern. The lifetime risk of any osteoporotic fracture is very high (40-50% in women and 13-22% in men). Fractures are associated with significant mortality and morbidity and represent a substantial economic burden to society. Bisphosphonates (alendronate, etidronate, risedronate and ibandronate) are indicated for the treatment and prevention of osteoporosis but are costly compared with other treatments, such as vitamin D and calcium. Our search identified 23 studies evaluating the cost effectiveness of bisphosphonate therapy for the treatment and prevention of fragility fractures; these studies were from five geographical areas and employed a variety of comparators and assumptions. We identified 11 studies investigating bisphosphonates in women with low bone mineral density (BMD) [T-score >2.5 standard deviations {SDs} below normal {mean} peak values for young adults] and previous fractures, five studies investigating bisphosphonates in women with low BMD and no previous fracture, one study of bisphosphonates in women with osteopenia, five studies involving screening and two studies of bisphosphonates in special populations (women initiating corticosteroid treatment and men). In women with low BMD and previous fractures, bisphosphonate therapy was most cost effective in populations aged > or =70 years and was unlikely to be cost effective in populations aged < or =50 years. There was uncertainty concerning the cost effectiveness of bisphosphonates in such populations aged 60-69 years. In women with low BMD without previous fractures, treatment with alendronate or risedronate appeared to be cost effective across countries (UK, US, Denmark), but there was some uncertainty about the cost effectiveness of etidronate in patients in the highest age groups. Identifying risk factors for fractures through means such as spine radiographs to detect vertebral deformities improves the cost effectiveness of treatment. In women with osteopenia, alendronate therapy may be cost effective in women with a T-score of -2.4SD in the US. Screening for low BMD and treatment with alendronate or etidronate appears to be cost effective in postmenopausal women in general and in women with rheumatoid arthritis initiating corticosteroid therapy. Alendronate therapy without screening was also shown to be potentially cost effective in certain at-risk male populations, as well as in women initiating corticosteroid therapy after the age of 40 years. Decision makers in the US, UK and Sweden should consider funding the use of bisphosphonates for the prevention and treatment of osteoporosis in women aged >70 years, particularly if they have other risk factors for fracture. Further studies are required to make more definitive conclusions in other countries and patient populations. Screening strategies for low BMD followed by bisphosphonate treatment should also be considered in the general female population aged >65 years in the UK and US and in patients with rheumatoid arthritis initiating corticosteroid therapy.

Systematic review of the evidence on orthotic devices for the management of knee instability related to neuromuscular and central nervous system disorders.

OBJECTIVES: To assess the effectiveness of orthotic devices for the management of instability of the knee in adults with a neuromuscular disorder or central nervous system disorder. DESIGN: A systematic review of primary studies. SETTING: Community. PARTICIPANTS: Adults with a neuromuscular disorder or central nervous system disorder and impaired walking ability due to instability of the knee. INTERVENTIONS: Orthoses with the clinical aim of controlling knee instability, for example, knee-ankle-foot orthoses, ankle-foot orthoses and knee orthoses or mixed design with no restrictions in design or material. PRIMARY AND SECONDARY OUTCOME MEASURES: Condition-specific or generic patient-reported outcome measures assessing function, disability, independence, activities of daily living, quality of life or psychosocial outcomes; pain; walking ability; functional assessments; biomechanical analysis; adverse effects; usage; patient satisfaction and the acceptability of a device; and resource utilisation data. RESULTS: Twenty-one studies including 478 patients were included. Orthotic devices were evaluated in patients with postpolio syndrome, poststroke syndrome, inclusion body myositis and spinal cord injury. The review included 2 randomised controlled trials (RCTs), 3 non-randomised controlled studies and 16 case series. Most were small, single-centre studies with only 6 of 21 following patients for 1 year or longer. They met between one and five of nine quality criteria and reported methods and results poorly. They mainly assessed outcomes related to gait analysis and energy consumption with limited use of standardised, validated, patient-reported outcome measures. There was an absence of evidence on outcomes of direct importance to patients such as reduction in pain and falls. CONCLUSIONS: There is a need for high-quality research, particularly RCTs, of orthotic devices for knee instability related to neuromuscular and central nervous system conditions. This research should address outcomes important to patients. There may also be value in developing a national registry. REGISTRATION NUMBER SYSTEMATIC REVIEW: PROSPERO (CRD42014010180).

Comprehensive decision-analytic model and Bayesian value-of-information analysis: pentoxifylline in the treatment of chronic venous leg ulcers.

OBJECTIVE: To conduct a Bayesian value-of-information analysis of the cost effectiveness of pentoxifylline (vs placebo) as an adjunct to compression for venous leg ulcers. METHODS: A probabilistic Markov model was developed to estimate mean clinical benefits and costs associated with oral pentoxifylline (400mg three times daily) and placebo. Clinical data were obtained from a systematic review and synthesised using Bayesian methods. The decision uncertainty associated with the adoption of pentoxifylline as well as the maximum value associated with further research were estimated before and after the completion of the largest 'definitive' treatment trial. Resource use was obtained from a UK national audit and unit costs applied (pounds, 2004 values). RESULTS: The prior and posterior analyses suggest that pentoxifylline is a dominant therapy versus placebo. In the prior analysis, patients in the pentoxifylline group healed an average of 8.28 weeks quicker than patients in the placebo group (95% credibility interval [CI] 1.89, 14.56), had a 0.02 gain in QALYs (95% CI -0.12, 0.17) and an average reduction in cost of 153.4 pounds (95% CI -53.11, 354.9). Estimates of the uncertainty surrounding the cost effectiveness of pentoxifylline and the value of perfect information in both analyses did not suggest further research was justified. In the prior analysis, for willingness-to-pay values of 0 pounds, 100 pounds and 500 pounds per QALY gained, the estimated values of perfect information were 128,200 pounds, 127,100 pounds and 126,700 pounds, respectively. Incorporation of the information from the largest randomised controlled trial on pentoxifylline did improve the estimate of the clinical effect associated with this drug; however, the variation was not large enough to reverse either the decision regarding the dominance of pentoxifylline or the maximum value associated with further research. CONCLUSION: Bayesian value-of-information analysis represents a valuable tool for healthcare decision making. Had the results from this analysis been available before the largest trial was funded, a more efficient allocation of research and development resources could have been made.

Reporting Guidelines for the Use of Expert Judgement in Model-Based Economic Evaluations.

INTRODUCTION: Expert judgement has a role in model-based economic evaluations (EEs) of healthcare interventions. This study aimed to produce reporting criteria for two types of study design to use expert judgement in model-based EE: (i) an expert elicitation (quantitative) study; and (ii) a Delphi study to collate (qualitative) expert opinion. METHODS: A two-round online Delphi process identified the degree of consensus for four core definitions (expert; expert parameter values; expert elicitation study; expert opinion) and two sets of reporting criteria in a purposive sample of experts. The initial set of reporting criteria comprised 17 statements for reporting a study to elicit parameter values and/or distributions and 11 statements for reporting a Delphi survey to obtain expert opinion. Fifty experts were invited to become members of the Delphi process panel by e-mail. Data analysis summarised the extent of agreement (using a pre-defined 75 % 'consensus' threshold) on the definitions and suggested reporting criteria. Free-text comments were analysed using thematic analysis. RESULTS: The final panel comprised 12 experts. Consensus was achieved for the definitions of expert (88 %); expert parameter values (83 %); and expert elicitation study (83 %). The panel recommended criteria to use when reporting an expert elicitation study (16 criteria) and a Delphi study to collate expert opinion (11 criteria). CONCLUSION: This study has produced guidelines for reporting two types of study design to use expert judgement in model-based EE: (i) an expert elicitation study requiring 16 reporting criteria; and (ii) a Delphi study to collate expert opinion requiring 11 reporting criteria.

Orthotic management of instability of the knee related to neuromuscular and central nervous system disorders: systematic review, qualitative study, survey and costing analysis.

BACKGROUND: Patients who have knee instability that is associated with neuromuscular disease (NMD) and central nervous system (CNS) conditions can be treated using orthoses, such as knee-ankle-foot orthoses (KAFOs). OBJECTIVES: To assess existing evidence on the effectiveness of orthoses; patient perspectives; types of orthotic devices prescribed in the UK NHS; and associated costs. METHODS: Qualitative study of views of orthoses users - a qualitative in-depth interview study was undertaken. Data were analysed for thematic content. A coding scheme was developed and an inductive approach was used to identify themes. Systematic review - 18 databases were searched up to November 2014: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, Cumulative Index to Nursing and Allied Health, EMBASE, PASCAL, Scopus, Science Citation Index, BIOSIS Previews, Physiotherapy Evidence Database, Recal Legacy, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment database, Cochrane Central Register of Controlled Trials, Conference Proceedings Citation Index: Science, Health Management Consortium, ClinicalTrials.gov, International Clinical Trials Registry Platform and National Technical Information Service. Studies of adults using an orthosis for instability of the knee related to NMD or a CNS disorder were included. Data were extracted and quality was assessed by two researchers. Narrative synthesis was undertaken. Survey and costing analysis - a web survey of orthotists, physiotherapists and rehabilitation medicine physicians was undertaken. Telephone interviews with orthotists informed a costing analysis. RESULTS: Qualitative study - a total of 24 people participated. Potential for engagement in daily activities was of vital importance to patients; the extent to which their device enabled this was the yardstick by which it was measured. Patients' prime desired outcome was a reduction in pain, falls or trips, with improved balance and stability. Effectiveness, reliability, comfort and durability were the most valued features of orthoses. Many expressed frustration with perceived deficiencies in service provision relating to appointment and administrative systems and referral pathways. Systematic review - a total of 21 studies (478 participants) were included of people who had post-polio syndrome, inclusion body myositis, were post stroke or had spinal cord injury. The studies evaluated KAFOs (mainly carbon fibre), stance control KAFO and hip KAFOs. All of the studies were at risk of bias and, in general, were poorly reported. Survey and costing analysis - in total, 238 health-care professionals responded. A range of orthoses is prescribed for knee instability that is related to NMD or CNS conditions, approximately half being custom-made. At least 50% of respondents thought that comfort and confidence in mobility were extremely important treatment outcomes. The cost of individual KAFOs was highly variable, ranging from £73 to £3553. CONCLUSIONS: Various types of orthoses are used in the NHS to manage patients with NMD/CNS conditions and knee instability, both custom-made and prefabricated, of variable cost. Evidence on the effectiveness of the orthoses is limited, especially in relation to the outcomes that are important to orthoses users. LIMITATIONS: The population included was broad, limiting any in-depth consideration of specific conditions. The response rate to the survey was low, and the costing analysis was based on some assumptions that may not reflect the true costs of providing KAFOs. FUTURE WORK: Future work should include high-quality research on the effectiveness and cost-effectiveness of orthoses; development of a core set of outcome measures; further exploration of the views and experiences of patients; and the best models of service delivery. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014010180. The qualitative study is registered as Current Controlled Trials ISRCTN65240228. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Does assessing the value for money of therapeutic medical devices require a flexible approach?

Regulation criteria for licensing pharmaceuticals and medical devices (MDs) are asymmetric. This has affected the type, quantity and quality of the evidence produced in support of MDs. This paper has three objectives: to examine the reasons behind the current licensing criteria for MDs; to identify key methodological challenges associated with pre- and post-market evaluation of MDs and to assess the extent to which existing methods for the economic evaluation of pharmaceuticals can be applied to the evaluation of MDs. The belief that MDs cannot be properly evaluated stems from a combination of historical events and complexities in implementing rigorous RCTs in this field. Existing challenges to conduct sound economic evaluation of MDs have begun to be addressed in medical research using mixed research methods. While more challenging to implement, robust evaluations of therapeutic MDs can and need to be carried out to safeguard individual's wellbeing.

A review of the economic tools for assessing new medical devices.

Whereas the economic evaluation of pharmaceuticals is an established practice within international health technology assessment (HTA) and is often produced with the support of comprehensive methodological guidance, the equivalent procedure for medical devices is less developed. Medical devices, including diagnostic products, are a rapidly growing market in healthcare, with over 10,000 medical technology patent applications filed in Europe in 2012-nearly double the number filed for pharmaceuticals. This increase in the market place, in combination with the limited, or constricting, budgets that healthcare decision makers face, has led to a greater level of examination with respect to the economic evaluation of medical devices. However, methodological questions that arise due to the unique characteristics of medical devices have yet to be addressed fully. This review of journal publications and HTA guidance identified these characteristics and the challenges they may subsequently pose from an economic evaluation perspective. These unique features of devices can be grouped into four categories: (1) data quality issues; (2) learning curve; (3) measuring long-term outcomes from diagnostic devices; and (4) wider impact from organisational change. We review the current evaluation toolbox available to researchers and explore potential future approaches to improve the economic evaluation of medical devices.

VenUS IV (Venous leg Ulcer Study IV) - compression hosiery compared with compression bandaging in the treatment of venous leg ulcers: a randomised controlled trial, mixed-treatment comparison and decision-analytic model.

BACKGROUND: Compression is an effective and recommended treatment for venous leg ulcers. Although the four-layer bandage (4LB) is regarded as the gold standard compression system, it is recognised that the amount of compression delivered might be compromised by poor application technique. Also the bulky nature of the bandages might reduce ankle or leg mobility and make the wearing of shoes difficult. Two-layer compression hosiery systems are now available for the treatment of venous leg ulcers. Two-layer hosiery (HH) may be advantageous, as it has reduced bulk, which might enhance ankle or leg mobility and patient adherence. Some patients can also remove and reapply two-layer hosiery, which may encourage self-management and could reduce costs. However, little robust evidence exists about the effectiveness of two-layer hosiery for ulcer healing and no previous trials have compared two-layer hosiery delivering 'high' compression with the 4LB. OBJECTIVES: Part I To compare the clinical effectiveness and cost-effectiveness of HH and 4LB in terms of time to complete healing of venous leg ulcers. Part II To synthesise the relative effectiveness evidence (for ulcer healing) of high-compression treatments for venous leg ulcers using a mixed-treatment comparison (MTC). Part III To construct a decision-analytic model to assess the cost-effectiveness of high-compression treatments for venous leg ulcers. DESIGN: Part I A multicentred, pragmatic, two-arm, parallel, open randomised controlled trial (RCT) with an economic evaluation. Part II MTC using all relevant RCT data - including Venous leg Ulcer Study IV (VenUS IV). Part III A decision-analytic Markov model. SETTINGS: Part I Community nurse teams or services, general practitioner practices, leg ulcer clinics, tissue viability clinics or services and wound clinics within England and Northern Ireland. PARTICIPANTS: Part I Patients aged ≥ 18 years with a venous leg ulcer, who were willing and able to tolerate high compression. INTERVENTIONS: Part I Participants in the intervention group received HH. The control group received the 4LB, which was applied according to standard practice. Both treatments are designed to deliver 40 mmHg of compression at the ankle. Part II and III All relevant high-compression treatments including HH, the 4LB and the two-layer bandage (2LB). MAIN OUTCOME MEASURES: Part I The primary outcome measure was time to healing of the reference ulcer (blinded assessment). Part II Time to ulcer healing. Part III Quality-adjusted life-years (QALYs) and costs. RESULTS: Part I A total of 457 participants were recruited. There was no evidence of a difference in time to healing of the reference ulcer between groups in an adjusted analysis [hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.79 to 1.25; p = 0.96]. Time to ulcer recurrence was significantly shorter in the 4LB group (HR = 0.56, 95% CI 0.33 to 0.94; p = 0.026). In terms of cost-effectiveness, using QALYs as the measure of benefit, HH had a > 95% probability of being the most cost-effective treatment based on the within-trial analysis. Part II The MTC suggests that the 2LB has the highest probability of ulcer healing compared with other high-compression treatments. However, this evidence is categorised as low to very low quality. Part III Results suggested that the 2LB had the highest probability of being the most cost-effective high-compression treatment for venous leg ulcers. CONCLUSIONS: Trial data from VenUS IV found no evidence of a difference in venous ulcer healing between HH and the 4LB. HH may reduce ulcer recurrence rates compared with the 4LB and be a cost-effective treatment. When all available high-compression treatments were considered, the 2LB had the highest probability of being clinically effective and cost-effective. However, the underpinning evidence was sparse and more research is needed. Further research should thus focus on establishing, in a high-quality trial, the effectiveness of this compression system in particular. TRIAL REGISTRATION: Current Controlled Trials ISRCTN49373072. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 57. See the NIHR Journals Library website for further project information.

Methods to assess cost-effectiveness and value of further research when data are sparse: negative-pressure wound therapy for severe pressure ulcers.

Health care resources are scarce, and decisions have to be made about how to allocate funds. Often, these decisions are based on sparse or imperfect evidence. One such example is negative-pressure wound therapy (NPWT), which is a widely used treatment for severe pressure ulcers; however, there is currently no robust evidence that it is effective or cost-effective. This work considers the decision to adopt NPWT given a range of alternative treatments, using a decision analytic modeling approach. Literature searches were conducted to identify existing evidence on model parameters. Given the limited evidence base, a second source of evidence, beliefs elicited from experts, was used. Judgments from experts on relevant (uncertain) quantities were obtained through a formal elicitation exercise. Additionally, data derived from a pilot trial were also used to inform the model. The 3 sources of evidence were collated, and the impact of each on cost-effectiveness was evaluated. An analysis of the value of further information indicated that a randomized controlled trial may be worthwhile in reducing decision uncertainty, where from a set of alternative designs, a 3-arm trial with longer follow-up was estimated to be the most efficient. The analyses presented demonstrate how allocation decisions about medical technologies can be explicitly informed when data are sparse and how this kind of analyses can be used to guide future research prioritization, not only indicating whether further research is worthwhile but what type of research is needed and how it should be designed.

Cost effectiveness analysis of larval therapy for leg ulcers.

OBJECTIVE: To assess the cost effectiveness of larval therapy compared with hydrogel in the management of leg ulcers. DESIGN: Cost effectiveness and cost utility analyses carried out alongside a pragmatic multicentre, randomised, open trial with equal randomisation. Population Intention to treat population comprising 267 patients with a venous or mixed venous and arterial ulcers with at least 25% coverage of slough or necrotic tissue. INTERVENTIONS: Patients were randomly allocated to debridement with bagged larvae, loose larvae, or hydrogel. MAIN OUTCOME MEASURE: The time horizon was 12 months and costs were estimated from the UK National Health Service perspective. Cost effectiveness outcomes are expressed in terms of incremental costs per ulcer-free day (cost effectiveness analysis) and incremental costs per quality adjusted life years (cost utility analysis). RESULTS: The larvae arms were pooled for the main analysis. Treatment with larval therapy cost, on average, pound96.70 (euro109.61; $140.57) more per participant per year (95% confidence interval - pound491.9 to pound685.8) than treatment with hydrogel. Participants treated with larval therapy healed, on average, 2.42 days before those in the hydrogel arm (95% confidence interval -0.95 to 31.91 days) and had a slightly better health related quality of life, as the annual difference in QALYs was 0.011 (95% confidence interval -0.067 to 0.071). However, none of these differences was statistically significant. The incremental cost effectiveness ratio for the base case analysis was estimated at pound8826 per QALY gained and pound40 per ulcer-free day. Considerable uncertainty surrounds the outcome estimates. CONCLUSIONS: Debridement of sloughy or necrotic leg ulcers with larval therapy is likely to produce similar health benefits and have similar costs to treatment with hydrogel. TRIAL REGISTRATION: Current Controlled Trials ISRCTN55114812 and National Research Register N0484123692.

Systematic reviews and economic evaluations conducted for the National Institute for Health and Clinical Excellence in the United Kingdom: a game of two halves?

BACKGROUND: Decision analytic models, as used in economic evaluations, require data on several clinical parameters. The gold standard approach is to conduct a systematic review of the relevant clinical literature, although reviews of economic evaluations indicate that this is rarely done. Technology appraisals for the National Institute for Health and Clinical Excellence (NICE), which are fully funded, represent the best case scenario for the close integration of economic evaluations and systematic reviews. The objective of this study was to assess the extent to which the systematic review of the clinical literature informs the economic evaluation in NICE technology appraisals. METHODS: All NICE technology assessment reports (TARs) published between January 2003 and July 2006 were considered. Data were abstracted on the TAR topics, the primary measure of clinical effectiveness, the approach to pooling in the clinical review, the measure of economic benefit and the use, or non-use, of the systematic review in the economic evaluation. RESULTS: Forty-one TARs were published in the period studied, all of which contained a systematic review. Most of the economic evaluations (85 percent) were cost-utility analyses, reflecting NICE's guidelines for economic evaluation. In seventeen cases, the clinical data were not pooled in the review, owing to heterogeneity in the clinical data or the limited number of studies. In these cases, the economists used alternative approaches for estimating the key effectiveness parameter in the model. The results of the review (when pooled) were always used when the primary clinical effectiveness measure corresponded with the measure of economic benefit (e.g., survival). However, because preference-based quality of life measures are rarely included in clinical trials, the results of the systematic review were never directly used in the cost-utility analyses. Nevertheless, the outputs of the systematic review were used when the data were useful in estimating components of the quality-adjusted life-year (QALY) (e.g., the life-years gained, or the frequencies of health states to which QALYs could be assigned). Problems occurred mainly when the clinical data were not pooled, or when the measure of clinical benefit could not be converted into health states to which QALYs could be assigned. CONCLUSIONS: Economic evaluations can benefit from systematic reviews of the clinical literature. However, such reviews are not a panacea for conducting a good economic evaluation. Much of the relevant data for estimating QALYs are not contained in such reviews and the chosen method for summarizing the clinical data may inhibit the assessment of economic benefit. Problems would be reduced if those undertaking the technology assessments discussed the data requirements for the economic model at an early stage.

Economic evaluations of interventions for the prevention and treatment of osteoporosis: a structured review of the literature.

Economic evaluations are increasingly being used by decision-makers to estimate the cost-effectiveness of interventions. The objective of this study was to conduct a structured review of economic evaluations of interventions to prevent and treat osteoporosis. Articles were identified independently by two reviewers through searches on MEDLINE, the bibliographies of reviews and identified economic models, and expert opinion, using predefined inclusion and exclusion criteria. Data on country, type and level of interventions, type of fractures, interventions, study population and the authors' stated conclusions were extracted. Forty-two relevant studies were identified. The majority of studies (71%) were conducted in Sweden, the UK and the US. The main interventions investigated were hormone replacement therapy (27%), bisphosphonates (17%) and combinations of vitamin D and calcium (16%). In 38% of studies, hip fracture was the sole fracture outcome. Eighty-eight percent (88%) of studies investigated female populations only. A relatively large number of economic evaluations were identified in the field of osteoporosis. Major changes have recently occurred in the treatment of this disease, following the publication of the results of the Women's Health Initiative trial. Methodological developments in economic evaluations, such as the use of probabilistic sensitivity analysis and cost-effectiveness acceptability curves, have also taken place. Such changes are reflected in the studies that were reviewed. The development of economic models should be an iterative process that incorporates new information, whether clinical or methodological, as it becomes available.

Health-care decision-making processes in Latin America: problems and prospects for the use of economic evaluation.

OBJECTIVES: The use of economic evaluation studies (EE) in the decision-making process within the health-care system of nine Latin American (LA) and three European countries was investigated. The aim was to identify the opportunities, obstacles, and changes needed to facilitate the introduction of EE as a formal tool in health-care decision-making processes in LA. METHODS: A comparative study was conducted based on existing literature and information provided through a questionnaire applied to decision makers in Argentina, Brazil, Colombia, Cuba, Mexico, Nicaragua, Peru, Portugal Spain, United Kingdom, Uruguay, and Venezuela. Systematic electronic searches of HEED, NHS EED, and LILACS were conducted to identify published economic evaluation studies in LA from 1982 onward. RESULTS: There is relatively little evidence of the conduct and use of EE within the health care systems in LA. Electronic searches retrieved 554 records; however, only 93 were EE. In the nine LA participating countries, broad allocation of health-care resources is primarily based on political criteria, historical records, geographical areas, and specific groups of patients and diseases. Public-health provision and inclusion of services in health-insurance package are responsibilities of the Ministry of Health. Decisions regarding the purchase of medicines are primarily made through public tenders, and mainly based on differences in clinical efficacy and the price of health technologies of interest. CONCLUSIONS: To expedite the process of incorporating EE as a formal tool to inform decision-making processes within the health-care systems in LA countries, two main conditions need to be fulfilled. First, adequate resources and skills need to be available to conduct EE of good quality. Second, decision-making procedures need to be modified to accommodate "evidence-based" approaches such as EE.