Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction.

BACKGROUND: Whether revascularization by percutaneous coronary intervention (PCI) can improve event-free survival and left ventricular function in patients with severe ischemic left ventricular systolic dysfunction, as compared with optimal medical therapy (i.e., individually adjusted pharmacologic and device therapy for heart failure) alone, is unknown. METHODS: We randomly assigned patients with a left ventricular ejection fraction of 35% or less, extensive coronary artery disease amenable to PCI, and demonstrable myocardial viability to a strategy of either PCI plus optimal medical therapy (PCI group) or optimal medical therapy alone (optimal-medical-therapy group). The primary composite outcome was death from any cause or hospitalization for heart failure. Major secondary outcomes were left ventricular ejection fraction at 6 and 12 months and quality-of-life scores. RESULTS: A total of 700 patients underwent randomization - 347 were assigned to the PCI group and 353 to the optimal-medical-therapy group. Over a median of 41 months, a primary-outcome event occurred in 129 patients (37.2%) in the PCI group and in 134 patients (38.0%) in the optimal-medical-therapy group (hazard ratio, 0.99; 95% confidence interval [CI], 0.78 to 1.27; P = 0.96). The left ventricular ejection fraction was similar in the two groups at 6 months (mean difference, -1.6 percentage points; 95% CI, -3.7 to 0.5) and at 12 months (mean difference, 0.9 percentage points; 95% CI, -1.7 to 3.4). Quality-of-life scores at 6 and 12 months appeared to favor the PCI group, but the difference had diminished at 24 months. CONCLUSIONS: Among patients with severe ischemic left ventricular systolic dysfunction who received optimal medical therapy, revascularization by PCI did not result in a lower incidence of death from any cause or hospitalization for heart failure. (Funded by the National Institute for Health and Care Research Health Technology Assessment Program; REVIVED-BCIS2 ClinicalTrials.gov number, NCT01920048.).

High-throughput, non-invasive prenatal testing for fetal rhesus D status in RhD-negative women: a systematic review and meta-analysis.

BACKGROUND: High-throughput non-invasive prenatal testing (NIPT) for fetal Rhesus D (RhD) status could avoid unnecessary treatment with anti-D immunoglobulin for RhD-negative women found to be carrying an RhD-negative fetus. We aimed to assess the diagnostic accuracy of high-throughput NIPT for fetal RhD status in RhD-negative women not known to be sensitized to the RhD antigen, by performing a systematic review and meta-analysis. METHODS: Prospective cohort studies of high-throughput NIPT used to determine fetal RhD status were included. The eligible population were pregnant women who were RhD negative and not known to be sensitized to RhD antigen. The index test was high-throughput, NIPT cell-free fetal DNA tests of maternal plasma used to determine fetal RhD status. The reference standard considered was serologic cord blood testing at birth. Databases including MEDLINE, EMBASE, and Science Citation Index were searched up to February 2016. Two reviewers independently screened titles and abstracts and assessed full texts identified as potentially relevant. Risk of bias was assessed using QUADAS-2. The bivariate and hierarchical summary receiver-operating characteristic (HSROC) models were fitted to calculate summary estimates of sensitivity, specificity, false positive and false negative rates, and the associated 95% confidence intervals (CIs). RESULTS: A total of 3921 references records were identified through electronic searches. Eight studies were included in the systematic review. Six studies were judged to be at low risk of bias. The HSROC models demonstrated high diagnostic performance of high-throughput NIPT testing for women tested at or after 11 weeks gestation. In the primary analysis for diagnostic accuracy, women with an inconclusive test result were treated as having tested positive. The false negative rate (incorrectly classed as RhD negative) was 0.34% (95% CI 0.15 to 0.76) and the false positive rate (incorrectly classed as RhD positive) was 3.86% (95% CI 2.54 to 5.82). There was limited evidence for non-white women and multiple pregnancies. CONCLUSIONS: High-throughput NIPT is sufficiently accurate to detect fetal RhD status in RhD-negative women and would considerably reduce unnecessary treatment with routine anti-D immunoglobulin. The applicability of these findings to non-white women and women with multiple pregnancies is uncertain.

Methods for network meta-analysis of continuous outcomes using individual patient data: a case study in acupuncture for chronic pain.

BACKGROUND: Network meta-analysis methods, which are an extension of the standard pair-wise synthesis framework, allow for the simultaneous comparison of multiple interventions and consideration of the entire body of evidence in a single statistical model. There are well-established advantages to using individual patient data to perform network meta-analysis and methods for network meta-analysis of individual patient data have already been developed for dichotomous and time-to-event data. This paper describes appropriate methods for the network meta-analysis of individual patient data on continuous outcomes. METHODS: This paper introduces and describes network meta-analysis of individual patient data models for continuous outcomes using the analysis of covariance framework. Comparisons are made between this approach and change score and final score only approaches, which are frequently used and have been proposed in the methodological literature. A motivating example on the effectiveness of acupuncture for chronic pain is used to demonstrate the methods. Individual patient data on 28 randomised controlled trials were synthesised. Consistency of endpoints across the evidence base was obtained through standardisation and mapping exercises. RESULTS: Individual patient data availability avoided the use of non-baseline-adjusted models, allowing instead for analysis of covariance models to be applied and thus improving the precision of treatment effect estimates while adjusting for baseline imbalance. CONCLUSIONS: The network meta-analysis of individual patient data using the analysis of covariance approach is advocated to be the most appropriate modelling approach for network meta-analysis of continuous outcomes, particularly in the presence of baseline imbalance. Further methods developments are required to address the challenge of analysing aggregate level data in the presence of baseline imbalance.

Point prevalence of complex wounds in a defined United Kingdom population.

Complex wounds (superficial-, partial-, or full-thickness skin loss wounds healing by secondary intention) are common; however, there is a lack of high-quality, contemporary epidemiological data. This paper presents point prevalence estimates for complex wounds overall as well as for individual types. A multiservice, cross-sectional survey was undertaken across a United Kingdom city (Leeds, population 751,485) during 2 weeks in spring of 2011. The mean age of people with complex wounds was approximately 70 years, standard deviation 19.41. The point prevalence of complex wounds was 1.47 per 1,000 of the population, 95% confidence interval 1.38 to 1.56. While pressure ulcers and leg ulcers were the most frequent, one in five people in the sample population had a less common wound type. Surveys confined to people with specific types of wound would underestimate the overall impact of complex wounds on the population and health care resources.

Network meta-analysis of (individual patient) time to event data alongside (aggregate) count data.

BACKGROUND: Network meta-analysis methods extend the standard pair-wise framework to allow simultaneous comparison of multiple interventions in a single statistical model. Despite published work on network meta-analysis mainly focussing on the synthesis of aggregate data, methods have been developed that allow the use of individual patient-level data specifically when outcomes are dichotomous or continuous. This paper focuses on the synthesis of individual patient-level and summary time to event data, motivated by a real data example looking at the effectiveness of high compression treatments on the healing of venous leg ulcers. METHODS: This paper introduces a novel network meta-analysis modelling approach that allows individual patient-level (time to event with censoring) and summary-level data (event count for a given follow-up time) to be synthesised jointly by assuming an underlying, common, distribution of time to healing. Alternative model assumptions were tested within the motivating example. Model fit and adequacy measures were used to compare and select models. RESULTS: Due to the availability of individual patient-level data in our example we were able to use a Weibull distribution to describe time to healing; otherwise, we would have been limited to specifying a uniparametric distribution. Absolute effectiveness estimates were more sensitive than relative effectiveness estimates to a range of alternative specifications for the model. CONCLUSIONS: The synthesis of time to event data considering individual patient-level data provides modelling flexibility, and can be particularly important when absolute effectiveness estimates, and not just relative effect estimates, are of interest.

Cost-effectiveness of interventions for increasing the possession of functioning smoke alarms in households with pre-school children: a modelling study.

BACKGROUND: The UK has one of the highest rates for deaths from fire and flames in children aged 0-14 years compared to other high income countries. Evidence shows that smoke alarms can reduce the risk of fire-related injury but little exists on their cost-effectiveness. We aimed to compare the cost effectiveness of different interventions for the uptake of 'functioning' smoke alarms and consequently for the prevention of fire-related injuries in children in the UK. METHODS: We carried out a decision model-based probabilistic cost-effectiveness analysis. We used a hypothetical population of newborns and evaluated the impact of living in a household with or without a functioning smoke alarm during the first 5 years of their life on overall lifetime costs and quality of life from a public health perspective. We compared seven interventions, ranging from usual care to more complex interventions comprising of education, free/low cost equipment giveaway, equipment fitting and/or home safety inspection. RESULTS: Education and free/low cost equipment was the most cost-effective intervention with an estimated incremental cost-effectiveness ratio of £34,200 per QALY gained compared to usual care. This was reduced to approximately £4,500 per QALY gained when 1.8 children under the age of 5 were assumed per household. CONCLUSIONS: Assessing cost-effectiveness, as well as effectiveness, is important in a public sector system operating under a fixed budget restraint. As highlighted in this study, the more effective interventions (in this case the more complex interventions) may not necessarily be the ones considered the most cost-effective.

Challenges and opportunities for identifying people with Familial hypercholesterolaemia in the UK: Evidence from the National FH PASS database.

BACKGROUND: Familial Hypercholesterolaemia (FH) is a monogenic disorder that causes high levels of low-density lipoprotein (LDL) cholesterol. Cascade testing, where relatives of known individuals with FH ('index') are genetically tested, is effective and cost-effective, but implementation in the UK varies. OBJECTIVE: This study aims to provide evidence on current UK FH cascade yields and to identify common obstacles cascade services face and individual- and service-level predictors of success. METHODS: Electronic health records from 875 index families and 5,958 linked relatives in the UK's Welsh and Wessex FH services (2019) were used to explore causes for non-testing and to estimate testing rates, detection yields, and how relative characteristics and contact methods relate to the probability of relatives being tested (using logistic regression). RESULTS: In Wales (Wessex), families included 7.35 (7.01) members on average, with 2.41 (1.66) relatives tested and 1.35 (0.96) diagnosed with FH per index. Cascade testing is limited by individualised circumstances (too young, not at-risk, etc.) and FH services' reach, with approximately one in four relatives out-of-area. In Wales, first-degree relatives (odds ratio (OR):1.55 [95 % confidence interval (CI):1.28,1.88]) and directly contacted relatives (OR:2.11 [CI:1.66,2.69]) were more likely to be tested. In Wales and Wessex, women were more likely to be tested than men (ORs:1.53 [CI:1.28,1.85] and 1.74 [CI:1.32,2.27]). CONCLUSION: In Wales and Wessex less than a third of relatives of an index are tested for FH. Improvements are likely possible by integrating geographically dispersed families into cascade testing, services directly contacting relatives where possible, and finding new ways to encourage participation, particularly amongst men.

Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction: Cost-Effectiveness Analysis of the REVIVED-BCIS2 Trial.

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently undertaken in patients with ischemic left ventricular systolic dysfunction. The REVIVED (Revascularization for Ischemic Ventricular Dysfunction)-BCIS2 (British Cardiovascular Society-2) trial concluded that PCI did not reduce the incidence of all-cause death or heart failure hospitalization; however, patients assigned to PCI reported better initial health-related quality of life than those assigned to optimal medical therapy (OMT) alone. The aim of this study was to assess the cost-effectiveness of PCI+OMT compared with OMT alone. METHODS: REVIVED-BCIS2 was a prospective, multicenter UK trial, which randomized patients with severe ischemic left ventricular systolic dysfunction to either PCI+OMT or OMT alone. Health care resource use (including planned and unplanned revascularizations, medication, device implantation, and heart failure hospitalizations) and health outcomes data (EuroQol 5-dimension 5-level questionnaire) on each patient were collected at baseline and up to 8 years post-randomization. Resource use was costed using publicly available national unit costs. Within the trial, mean total costs and quality-adjusted life-years (QALYs) were estimated from the perspective of the UK health system. Cost-effectiveness was evaluated using estimated mean costs and QALYs in both groups. Regression analysis was used to adjust for clinically relevant predictors. RESULTS: Between 2013 and 2020, 700 patients were recruited (mean age: PCI+OMT=70 years, OMT=68 years; male (%): PCI+OMT=87, OMT=88); median follow-up was 3.4 years. Over all follow-ups, patients undergoing PCI yielded similar health benefits at higher costs compared with OMT alone (PCI+OMT: 4.14 QALYs, £22 352; OMT alone: 4.16 QALYs, £15 569; difference: -0.015, £6782). For both groups, most health resource consumption occurred in the first 2 years post-randomization. Probabilistic results showed that the probability of PCI being cost-effective was 0. CONCLUSIONS: A minimal difference in total QALYs was identified between arms, and PCI+OMT was not cost-effective compared with OMT, given its additional cost. A strategy of routine PCI to treat ischemic left ventricular systolic dysfunction does not seem to be a justifiable use of health care resources in the United Kingdom. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920048.

How does cholesterol burden change the case for investing in familial hypercholesterolaemia? A cost-effectiveness analysis.

BACKGROUND AND AIMS: This study aimed to ascertain how the long-term benefits and costs of diagnosis and treatment of familial hypercholesterolaemia (FH) vary by prognostic factors and 'cholesterol burden', which is the effect of long-term exposure to low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) risk. METHODS: A new cost-effectiveness model was developed from the perspective of the UK National Health Service (NHS), informed by routine data from individuals with FH. The primary outcome was net health gain (i.e., health benefits net of the losses due to costs), expressed in quality-adjusted life years (QALYs) at the £15,000/QALY threshold. Prognostic factors included pre-treatment LDL-C, age, gender, and CVD history. RESULTS: If cholesterol burden is considered, diagnosis resulted in positive net health gain (i.e., it is cost-effective) in all individuals with pre-treatment LDL-C ≥ 4 mmol/L, and in those with pre-treatment LDL-C ≥ 2 mmol/L aged ≥50 years or who have CVD history. If cholesterol burden is not considered, diagnosis resulted in lower net health gain, but still positive in children aged 10 years with pre-treatment LDL-C ≥ 6 mmol/L and adults aged 30 years with pre-treatment LDL-C ≥ 4 mmol/L. CONCLUSIONS: Diagnosis and treatment of most people with FH results in large net health gains, particularly in those with higher pre-treatment LDL-C. Economic evaluations of FH interventions should consider the sensitivity of the study conclusions to cholesterol burden, particularly where interventions target younger patients, and explicitly consider prognostic factors such as pre-treatment LDL-C, age, and CVD history.

Network meta-analysis to evaluate the effectiveness of interventions to increase the uptake of smoke alarms.

This study is the first known to use network meta-analysis to simultaneously evaluate the effectiveness of interventions to increase the prevalence of functioning smoke alarms in households with children. The authors identified 24 primary studies from a systematic review of reviews and of more recently published primary studies, of which 23 (17 randomized controlled trials and 6 nonrandomized comparative studies) were included in 1 of the following 2 network meta-analyses: 1) possession of a functioning alarm: interventions that were more "intensive" (i.e., included components providing equipment (with or without fitting), home inspection, or both, in addition to education) generally were more effective. The intervention containing all of the aforementioned components was identified as being the most likely to be the most effective (probability (best) = 0.66), with an odds ratio versus usual care of 7.15 (95% credible interval: 2.40, 22.73); 2) type of battery-powered alarms: ionization alarms with lithium batteries were most likely to be the best type for increasing functioning possession (probability (best) = 0.69). Smoke alarm promotion programs should ensure they provide the combination of interventions most likely to be effective.

Mixed treatment comparisons using aggregate and individual participant level data.

Mixed treatment comparisons (MTC) extend the traditional pair-wise meta-analytic framework to synthesize information on more than two interventions. Although most MTCs use aggregate data (AD), a proportion of the evidence base might be available at the individual level (IPD). We develop a series of novel Bayesian statistical MTC models to allow for the simultaneous synthesis of IPD and AD, potentially incorporating study and individual level covariates. The effectiveness of different interventions to increase the provision of functioning smoke alarms in households with children was used as a motivating dataset. This included 20 studies (11 AD and 9 IPD), including 11 500 participants. Incorporating the IPD into the network allowed the inclusion of information on subject level covariates, which produced markedly more accurate treatment-covariate interaction estimates than an analysis solely on the AD from all studies. Including evidence at the IPD level in the MTC is desirable when exploring participant level covariates; even when IPD is available only for a fraction of the studies. Such modelling may not only reduce inconsistencies within networks of trials but also assist the estimation of intervention subgroup effects to guide more individualised treatment decisions.

Deriving input parameters for cost-effectiveness modeling: taxonomy of data types and approaches to their statistical synthesis.

BACKGROUND: The evidence base informing economic evaluation models is rarely derived from a single source. Researchers are typically expected to identify and combine available data to inform the estimation of model parameters for a particular decision problem. The absence of clear guidelines on what data can be used and how to effectively synthesize this evidence base under different scenarios inevitably leads to different approaches being used by different modelers. OBJECTIVES: The aim of this article is to produce a taxonomy that can help modelers identify the most appropriate methods to use when synthesizing the available data for a given model parameter. METHODS: This article developed a taxonomy based on possible scenarios faced by the analyst when dealing with the available evidence. While mainly focusing on clinical effectiveness parameters, this article also discusses strategies relevant to other key input parameters in any economic model (i.e., disease natural history, resource use/costs, and preferences). RESULTS: The taxonomy categorizes the evidence base for health economic modeling according to whether 1) single or multiple data sources are available, 2) individual or aggregate data are available (or both), or 3) individual or multiple decision model parameters are to be estimated from the data. References to examples of the key methodological developments for each entry in the taxonomy together with citations to where such methods have been used in practice are provided throughout. CONCLUSIONS: The use of the taxonomy developed in this article hopes to improve the quality of the synthesis of evidence informing decision models by bringing to the attention of health economics modelers recent methodological developments in this field.

Digital interventions in mental health: evidence syntheses and economic modelling.

BACKGROUND: Economic evaluations provide evidence on whether or not digital interventions offer value for money, based on their costs and outcomes relative to the costs and outcomes of alternatives. OBJECTIVES: (1) Evaluate and summarise published economic studies about digital interventions across different technologies, therapies, comparators and mental health conditions; (2) synthesise clinical evidence about digital interventions for an exemplar mental health condition; (3) construct an economic model for the same exemplar mental health condition using the previously synthesised clinical evidence; and (4) consult with stakeholders about how they understand and assess the value of digital interventions. METHODS: We completed four work packages: (1) a systematic review and quality assessment of economic studies about digital interventions; (2) a systematic review and network meta-analysis of randomised controlled trials on digital interventions for generalised anxiety disorder; (3) an economic model and value-of-information analysis on digital interventions for generalised anxiety disorder; and (4) a series of knowledge exchange face-to-face and digital seminars with stakeholders. RESULTS: In work package 1, we reviewed 76 economic evaluations: 11 economic models and 65 within-trial analyses. Although the results of the studies are not directly comparable because they used different methods, the overall picture suggests that digital interventions are likely to be cost-effective, compared with no intervention and non-therapeutic controls, whereas the value of digital interventions compared with face-to-face therapy or printed manuals is unclear. In work package 2, we carried out two network meta-analyses of 20 randomised controlled trials of digital interventions for generalised anxiety disorder with a total of 2350 participants. The results were used to inform our economic model, but when considered on their own they were inconclusive because of the very wide confidence intervals. In work package 3, our decision-analytic model found that digital interventions for generalised anxiety disorder were associated with lower net monetary benefit than medication and face-to-face therapy, but greater net monetary benefit than non-therapeutic controls and no intervention. Value for money was driven by clinical outcomes rather than by intervention costs, and a value-of-information analysis suggested that uncertainty in the treatment effect had the greatest value (£12.9B). In work package 4, stakeholders identified several areas of benefits and costs of digital interventions that are important to them, including safety, sustainability and reducing waiting times. Four factors may influence their decisions to use digital interventions, other than costs and outcomes: increasing patient choice, reaching underserved populations, enabling continuous care and accepting the 'inevitability of going digital'. LIMITATIONS: There was substantial uncertainty around effect estimates of digital interventions compared with alternatives. This uncertainty was driven by the small number of studies informing most comparisons, the small samples in some of these studies and the studies' high risk of bias. CONCLUSIONS: Digital interventions may offer good value for money as an alternative to 'doing nothing' or 'doing something non-therapeutic' (e.g. monitoring or having a general discussion), but their added value compared with medication, face-to-face therapy and printed manuals is uncertain. Clinical outcomes rather than intervention costs drive 'value for money'. FUTURE WORK: There is a need to develop digital interventions that are more effective, rather than just cheaper, than their alternatives. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018105837. 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. 26, No. 1. See the NIHR Journals Library website for further project information.

Digital interventions are activities accessed via technology platforms (e.g. computers, smartphones and virtual reality) that can improve users' mental health and reduce addiction problems. To assess whether or not digital interventions offer 'value for money', we needed to compare their costs and outcomes with the costs and outcomes of alternatives, such as face-to-face therapy and medication. This was done through economic evaluations. This project consisted of four work packages. In work package 1, we reviewed 76 published economic evaluations of digital interventions for different mental health and addiction problems. We could not directly compare their results because of differences in the methods that were used, but the overall picture suggested that digital interventions could offer good value for money as an alternative to 'doing nothing' or simply monitoring someone or giving them general information. The picture was unclear when digital interventions were compared with face-to-face therapy. In work package 2, we pooled research studies that evaluated the outcomes of digital interventions in reducing anxiety and worry; the results were inconclusive because we were uncertain about the differences in outcomes between digital interventions and alternatives. In work package 3, an economic model suggested that value for money in digital interventions is driven by how good they are and not by how much they cost. In work package 4, we presented our methods and results to service users, mental health professionals and researchers who wanted to know more about the value of digital interventions for specific groups (e.g. children and older adults) and for outcomes other than reducing symptoms (e.g. reducing waiting times for treatment and improving attendance for therapy). Finally, the stakeholders highlighted four factors that may influence their decisions to use digital interventions, other than costs and outcomes: increasing choice, reaching underserved populations, enabling continuous care and accepting the 'inevitability of going digital'.

Digital Interventions for Generalized Anxiety Disorder (GAD): Systematic Review and Network Meta-Analysis.

Background: Generalized anxiety disorder is the most common mental health condition based on weekly prevalence. Digital interventions have been used as alternatives or as supplements to conventional therapies to improve access, patient choice, and clinical outcomes. Little is known about their comparative effectiveness for generalized anxiety disorder. Methods: We conducted a systematic review and network meta-analysis of randomized controlled trials comparing digital interventions with medication, non-digital interventions, non-therapeutic controls, and no intervention. Results: We included 21 randomized controlled trials with a total of 2,350 participants from generalized anxiety disorder populations. Pooled outcomes using analysis of Covariance and rankograms based on the surface under the cumulative ranking curves indicated that antidepressant medication and group therapy had a higher probability than digital interventions of being the "best" intervention. Supported digital interventions were not necessarily "better" than unsupported (pure self-help) ones. Conclusions: Due to very wide confidence intervals, network meta-analysis results were inconclusive as to whether digital interventions are better than no intervention and non-therapeutic active controls, or whether they confer an additional benefit to standard therapy. Future research needs to compare digital interventions with one-to-one therapy and with manualized non-digital self-help and to include antidepressant medication as a treatment comparator and effect modifier.

Effects of Bladder Cancer on UK Healthcare Costs and Patient Health-Related Quality of Life: Evidence From the BOXIT Trial.

BACKGROUND: Limited evidence exists regarding the cost and health-related quality of life (HRQoL) effects of non-muscle-invasive bladder cancer (NMIBC) recurrence and progression to muscle-invasive bladder cancer (MIBC). We examined these effects using evidence from a recent randomized control trial. MATERIAL AND METHODS: The costs and HRQoL associated with bladder cancer were assessed using data from the BOXIT trial (bladder COX-2 inhibition trial; n = 472). The cost and HRQoL effects from clinical events were estimated using generalized estimating equations. The costs were derived from the recorded resource usage and UK unit costs. HRQoL was assessed using the EQ-5D-3L and reported UK preference tariffs. The events were categorized using the TMN classification. RESULTS: Cases of grade 3 recurrence and progression were associated with statistically significant HRQoL decrements (-0.08; 95% confidence interval [CI], -0.13 to -0.03; and -0.10; 95% CI, -0.17 to -0.03, respectively). The 3-year average cost per NMIBC patient was estimated at £8735 (95% CI, 8325-9145). Cases of grade 1, 2, and 3 recurrence were associated with annual cost effects of £1218 (95% CI, 403-2033), £1677 (95% CI, 920-2433), and £3957 (95% CI, 2332-5583), respectively. Progression to MIBC was associated with an average increase in costs of £5407 (95% CI, 2663-8152). CONCLUSION: Evidence from the BOXIT trial suggests that patients with NMIBC will both experience decrements in HRQoL and incur significant costs, especially in the event of a grade 3 recurrence or a progression to MIBC.

The Value of Further Research: The Added Value of Individual-Participant Level Data.

Judgements based on average cost-effectiveness estimates may disguise significant heterogeneity in net health outcomes. Decisions about coverage of new interventions are often more efficient when they consider between-patient heterogeneity, which is usually operationalized as different selections for different subgroups. While most model-based cost-effectiveness studies are populated with aggregated-level sub-group estimates, individual-level data are recognized as the best source of evidence to produce unbiased and efficient estimates to explore this heterogeneity. This paper extends a previously published framework to assesses the added value of having access to individual-level data, compared to using aggregate-level data only, in the absence/presence of mutually exclusive population subgroups. Supported by a case study on the cost-effectiveness of interventions to increase uptake of smoke-alarms, the extended framework provided a quantification of the benefits foregone of not using individual-level data, pointed to the optimal number of subgroups and where further research should be undertaken. Although not indicating changes in reimbursement decisions, results showed that irrespective of using aggregate or individual-level data, no substantial additional gains are obtained if more than two subgroups are taken into account. However, depending on the evidence type used, different subgroups are revealed as warranting larger research funds. The use of individual-level data, rather than aggregate, may however influence not only the extent to which an appropriate understanding of existing heterogeneity is attained, but, more importantly, it may shape approval decisions for particular population subgroups and judgements of future research.

Brodalumab for the Treatment of Moderate-to-Severe Plaque Psoriasis: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal.

As part of the National Institute for Health and Care Excellence single technology appraisal process, brodalumab was assessed to determine the clinical and cost effectiveness of its use in the treatment of moderate-to-severe plaque psoriasis. The Centre for Reviews and Dissemination and the Centre for Health Economics Technology Assessment Group at the University of York were commissioned to act as the independent Evidence Review Group. This article provides a summary of the Evidence Review Group's review of the company's submission, the Evidence Review Group report and the National Institute for Health and Care Excellence Appraisal Committee's subsequent guidance issued in March 2018. The main clinical effectiveness data were derived from three well-conducted, multicentre, double-blind randomised controlled trials. The trials demonstrated that brodalumab statistically significantly reduced the severity of psoriasis and its impact on health-related quality of life, compared with placebo, at 12 weeks. In comparison with ustekinumab, statistically significantly more patients taking brodalumab had reduced psoriasis severity at 12 weeks. Psoriasis severity and quality of life also appeared improved at 52 weeks, although statistical significance was not assessed. Withdrawal rates were comparable to drug survival rates of other biological therapies and rates of adverse events were similar between brodalumab and ustekinumab. A network meta-analysis was presented, comparing brodalumab with other therapies available at the same point in the treatment pathway (i.e. in patients for whom standard systemic therapy or phototherapy is inadequately effective, not tolerated or contraindicated). The network meta-analysis ranked treatments in order of effectiveness, in terms of achieving different levels of Psoriasis Area and Severity Index response. The results indicated that brodalumab had a similar probability of response to ixekizumab, secukinumab and infliximab and a higher probability of response than ustekinumab, adalimumab, etanercept, apremilast, dimethyl fumarate and placebo. The company's economic model compared nine treatment sequences that included three lines of active therapy, consisting of brodalumab and other comparators recommended by the National Institute for Health and Care Excellence, followed by best supportive care. The sequence with brodalumab in the first-line position dominated sequences that started with adalimumab, infliximab, secukinumab and ustekinumab. The incremental cost-effectiveness ratio of the brodalumab sequence compared to less effective and non-dominated sequences ranged from £7145 (vs. the etanercept sequence) to £13,353 (vs. the dimethyl fumarate sequence) per quality-adjusted life-year gained. The incremental cost-effectiveness ratio for the more costly and effective ixekizumab sequence was £894,010 per quality-adjusted life-year gained compared to the brodalumab sequence. At a threshold of £20,000 per quality-adjusted life-year gained, the brodalumab sequence had the highest probability of being cost effective (96%). The main limitation of the company's economic model was the restrictive nature of the sequences compared. Twelve separate scenarios based on key uncertainties were explored by the Evidence Review Group. The only scenarios where brodalumab was ranked lower than first were not considered to be more appropriate or plausible than the assumptions or scenarios included in the company's base case. The treatment rankings identified in the Evidence Review Group's alternative base case were identical to those derived from the company's base case model. At the first National Institute for Health and Care Excellence Appraisal Committee meeting, the Committee concluded that brodalumab appears to be as effective as other anti-interleukin-17 agents and is cost effective, based on the discount agreed in the patient access scheme. Brodalumab is recommended as an option for treating adults with severe plaque psoriasis (defined by a total Psoriasis Area and Severity Index score of 10 or more and a Dermatology Life Quality Index score of more than 10) who have not responded to other systemic non-biological therapies. Brodalumab should be stopped at 12 weeks if the psoriasis has not responded adequately.

High-throughput non-invasive prenatal testing for fetal rhesus D status in RhD-negative women not known to be sensitised to the RhD antigen: a systematic review and economic evaluation.

BACKGROUND: High-throughput non-invasive prenatal testing (NIPT) for fetal rhesus (D antigen) (RhD) status could avoid unnecessary treatment with routine anti-D immunoglobulin for RhD-negative women carrying a RhD-negative fetus, although this may lead to an increased risk of RhD sensitisations. OBJECTIVES: To systematically review the evidence on the diagnostic accuracy, clinical effectiveness and implementation of high-throughput NIPT and to develop a cost-effectiveness model. METHODS: We searched MEDLINE and other databases, from inception to February 2016, for studies of high-throughput NIPT free-cell fetal deoxyribonucleic acid (DNA) tests of maternal plasma to determine fetal RhD status in RhD-negative pregnant women who were not known to be sensitised to the RhD antigen. Study quality was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) and A Cochrane Risk of Bias Assessment Tool: for Non-Randomised Studies of Interventions (ACROBAT-NRSI). Summary estimates of false-positive rates (FPRs) and false-negative rates (FNRs) were calculated using bivariate models. Clinical effectiveness evidence was used to conduct a simulation study. We developed a de novo probabilistic decision tree-based cohort model that considered four alternative ways in which the results of NIPT could guide the use of anti-D immunoglobulin antenatally and post partum. Sensitivity analyses (SAs) were conducted to address key uncertainties and model assumptions. RESULTS: Eight studies were included in the diagnostic accuracy review, seven studies were included in the clinical effectiveness review and 12 studies were included in the review of implementation. Meta-analyses included women mostly at or post 11 weeks' gestation. The pooled FNR (women at risk of sensitisation) was 0.34% [95% confidence interval (CI) 0.15% to 0.76%] and the pooled FPR (women needlessly receiving anti-D) was 3.86% (95% CI 2.54% to 5.82%). SAs did not materially alter the overall results. Data on clinical outcomes, including sensitisation rates, were limited. Our simulation suggests that NIPT could substantially reduce unnecessary use of antenatal anti-D with only a small increase in the risk of sensitisation. All large implementation studies suggested that large-scale implementation of high-throughput NIPT was feasible. Seven cost-effectiveness studies were included in the review, which found that the potential for the use of NIPT to produce cost savings was dependent on the cost of the test. Our de novo model suggested that high-throughput NIPT is likely to be cost saving compared with the current practice of providing routine antenatal anti-D prophylaxis to all women who are RhD negative. The extent of the cost saving appeared to be sufficient to outweigh the small increase in sensitisations. However, the magnitude of the cost saving is highly sensitive to the cost of NIPT itself. LIMITATIONS: There was very limited evidence relating to the clinical effectiveness of high-throughput NIPT, with no evidence on potential adverse effects. The generalisability of the findings to non-white women and multiple pregnancies is unclear. CONCLUSIONS: High-throughput NIPT is sufficiently accurate to detect fetal RhD status in RhD-negative women from 11 weeks' gestation and would considerably reduce unnecessary treatment with routine anti-D immunoglobulin, potentially resulting in cost savings of between £485,000 and £671,000 per 100,000 pregnancies if the cost of implementing NIPT is in line with that reflected in this evaluation. FUTURE WORK: Further research on the diagnostic accuracy of NIPT in non-white women is needed. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015029497. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Cost-effectiveness of adjunct non-pharmacological interventions for osteoarthritis of the knee.

BACKGROUND: There is limited information on the costs and benefits of alternative adjunct non-pharmacological treatments for knee osteoarthritis and little guidance on which should be prioritised for commissioning within the NHS. This study estimates the costs and benefits of acupuncture, braces, heat treatment, insoles, interferential therapy, laser/light therapy, manual therapy, neuromuscular electrical stimulation, pulsed electrical stimulation, pulsed electromagnetic fields, static magnets and transcutaneous electrical nerve Stimulation (TENS), based on all relevant data, to facilitate a more complete assessment of value. METHODS: Data from 88 randomised controlled trials including 7,507 patients were obtained from a systematic review. The studies reported a wide range of outcomes. These were converted into EQ-5D index values using prediction models, and synthesised using network meta-analysis. Analyses were conducted including firstly all trials and secondly only trials with low risk of selection bias. Resource use was estimated from trials, expert opinion and the literature. A decision analytic model synthesised all evidence to assess interventions over a typical treatment period (constant benefit over eight weeks or linear increase in effect over weeks zero to eight and dissipation over weeks eight to 16). RESULTS: When all trials are considered, TENS is cost-effective at thresholds of £20-30,000 per QALY with an incremental cost-effectiveness ratio of £2,690 per QALY vs. usual care. When trials with a low risk of selection bias are considered, acupuncture is cost-effective with an incremental cost-effectiveness ratio of £13,502 per QALY vs. TENS. The results of the analysis were sensitive to varying the intensity, with which interventions were delivered, and the magnitude and duration of intervention effects on EQ-5D. CONCLUSIONS: Using the £20,000 per QALY NICE threshold results in TENS being cost-effective if all trials are considered. If only higher quality trials are considered, acupuncture is cost-effective at this threshold, and thresholds down to £14,000 per QALY.

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.