Stereotactic radiotherapy for neovascular age-related macular degeneration (STAR): a pivotal, randomised, double-masked, sham-controlled device trial.

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The first-line therapy is anti-vascular endothelial growth factor (anti-VEGF) agents delivered by intravitreal injection. Ionising radiation mitigates key pathogenic processes underlying nAMD, and therefore has therapeutic potential. STAR aimed to assess whether stereotactic radiotherapy (SRT) reduces the number of anti-VEGF injections required, without sacrificing visual acuity. METHODS: This pivotal, randomised, double-masked, sham-controlled trial enrolled participants with pretreated chronic active nAMD from 30 UK hospitals. Participants were randomly allocated in a 2:1 ratio to 16-Gray (Gy) SRT delivered using a robotically controlled device or sham SRT, stratified by treatment centre. Eligible participants were aged 50 years or older and had chronic active nAMD, with at least three previous anti-VEGF injections, including at least one in the last 4 months. Participants and all trial and image reading centre staff were masked to treatment allocation, except one unmasked statistician. The primary outcome was the number of intravitreal ranibizumab injections required over 2 years, tested for superiority (fewer injections). The main secondary outcome was Early Treatment Diabetic Retinopathy Study visual acuity at two years, tested for non-inferiority (five-letter margin). The primary analysis used the intention-to-treat principle, and safety was analysed per-protocol on participants with available data. The study is registered with ClinicalTrials.gov (NCT02243878) and is closed for recruitment. FINDINGS: 411 participants enrolled between Jan 1, 2015, and Dec 27, 2019, and 274 were randomly allocated to the 16-Gy SRT group and 137 to the sham SRT group. 240 (58%) of all participants were female, and 171 (42%) of all participants were male. 241 participants in the 16-Gy SRT group and 118 participants in the sham group were included in the final analysis, and 409 patients were treated and formed the safety population, of whom two patients allocated to sham treatment erroneously received 16-Gy SRT. The SRT group received a mean of 10·7 injections (SD 6·3) over 2 years versus 13·3 injections (5·8) with sham, a reduction of 2·9 injections after adjusting for treatment centre (95% CI -4·2 to -1·6, p<0·0001). The SRT group best-corrected visual acuity change was non-inferior to sham (adjusted mean letter loss difference between groups, -1·7 letters [95% CI -4·2 to 0·8]). Adverse event rates were similar across groups, but reading centre-detected microvascular abnormalities occurred in 77 SRT-treated eyes (35%) and 13 (12%) sham-treated eyes. Overall, eyes with microvascular abnormalities tended to have better best-corrected visual acuity than those without. Fewer ranibizumab injections offset the cost of SRT, saving a mean of £565 per participant (95% CI -332 to 1483). INTERPRETATION: SRT can reduce ranibizumab treatment burden without compromising vision. FUNDING: Medical Research Council and National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme.

Effectiveness of nail bed repair in children with or without replacing the fingernail: NINJA multicentre randomized clinical trial.

BACKGROUND: Surgery for nail bed injuries in children is common. One of the key surgical decisions is whether to replace the nail plate following nail bed repair. The aim of this RCT was to assess the clinical effectiveness and cost-effectiveness of nail bed repair with fingernail replacement/substitution compared with repair without fingernail replacement. METHODS: A two-arm 1 : 1 parallel-group open multicentre superiority RCT was performed across 20 secondary-care hospitals in the UK. The co-primary outcomes were surgical-site infection at around 7 days after surgery and cosmetic appearance summary score at a minimum of 4 months. RESULTS: Some 451 children presenting with a suspected nail bed injury were recruited between July 2018 and July 2019; 224 were allocated to the nail-discarded arm, and 227 to the nail-replaced arm. There was no difference in the number of surgical-site infections at around 7 days between the two interventions or in cosmetic appearance. The mean total healthcare cost over the 4 months after surgery was €84 (95 per cent c.i. 34 to 140) lower for the nail-discarded arm than the nail-replaced arm (P < 0.001). CONCLUSION: After nail bed repair, discarding the fingernail was associated with similar rates of infection and cosmesis ratings as replacement of the finger nail, but was cost saving. Registration number: ISRCTN44551796 (http://www.controlled-trials.com).

Progressive exercise compared with best practice advice, with or without corticosteroid injection, for the treatment of patients with rotator cuff disorders (GRASP): a multicentre, pragmatic, 2 × 2 factorial, randomised controlled trial.

BACKGROUND: Corticosteroid injections and physiotherapy exercise programmes are commonly used to treat rotator cuff disorders but the treatments' effectiveness is uncertain. We aimed to compare the clinical effectiveness and cost-effectiveness of a progressive exercise programme with a single session of best practice physiotherapy advice, with or without corticosteroid injection, in adults with a rotator cuff disorder. METHODS: In this pragmatic, multicentre, superiority, randomised controlled trial (2 × 2 factorial), we recruited patients from 20 UK National Health Service trusts. We included patients aged 18 years or older with a rotator cuff disorder (new episode within the past 6 months). Patients were excluded if they had a history of significant shoulder trauma (eg, dislocation, fracture, or full-thickness tear requiring surgery), neurological disease affecting the shoulder, other shoulder conditions (eg, inflammatory arthritis, frozen shoulder, or glenohumeral joint instability), received corticosteroid injection or physiotherapy for shoulder pain in the past 6 months, or were being considered for surgery. Patients were randomly assigned (centralised computer-generated system, 1:1:1:1) to progressive exercise (≤6 sessions), best practice advice (one session), corticosteroid injection then progressive exercise, or corticosteroid injection then best practice advice. The primary outcome was the Shoulder Pain and Disability Index (SPADI) score over 12 months, analysed on an intention-to-treat basis (statistical significance set at 1%). The trial was registered with the International Standard Randomised Controlled Trial Register, ISRCTN16539266, and EuDRACT, 2016-002991-28. FINDINGS: Between March 10, 2017, and May 2, 2019, we screened 2287 patients. 708 patients were randomly assigned to progressive exercise (n=174), best practice advice (n=174), corticosteroid injection then progressive exercise (n=182), or corticosteroid injection then best practice advice (n=178). Over 12 months, SPADI data were available for 166 (95%) patients in the progressive exercise group, 164 (94%) in the best practice advice group, 177 (97%) in the corticosteroid injection then progressive exercise group, and 175 (98%) in the corticosteroid injection then best practice advice group. We found no evidence of a difference in SPADI score between progressive exercise and best practice advice when analysed over 12 months (adjusted mean difference -0·66 [99% CI -4·52 to 3·20]). We also found no evidence of a difference between corticosteroid injection compared with no injection when analysed over 12 months (-1·11 [-4·47 to 2·26]). No serious adverse events were reported. INTERPRETATION: Progressive exercise was not superior to a best practice advice session with a physiotherapist in improving shoulder pain and function. Subacromial corticosteroid injection provided no long-term benefit in patients with rotator cuff disorders. FUNDING: UK National Institute for Health Research Technology Assessment Programme.

Economic Evaluation of Factorial Trials: Cost-Utility Analysis of the Atorvastatin in Factorial With Omega EE90 Risk Reduction in Diabetes 2 × 2 × 2 Factorial Trial of Atorvastatin, Omega-3 Fish Oil, and Action Planning.

OBJECTIVES: We applied principles for conducting economic evaluations of factorial trials to a trial-based economic evaluation of a cluster-randomized 2 × 2 × 2 factorial trial. We assessed the cost-effectiveness of atorvastatin, omega-3 fish oil, and an action-planning leaflet, alone and in combination, from a UK National Health Service perspective. METHODS: The Atorvastatin in Factorial With Omega EE90 Risk Reduction in Diabetes (AFORRD) Trial randomized 800 patients with type 2 diabetes to atorvastatin, omega-3, or their respective placebos and randomized general practices to receive a leaflet-based action-planning intervention designed to improve compliance or standard care. The trial was conducted at 59 UK general practices. Sixteen-week outcomes for each trial participant were extrapolated for 70 years using the United Kingdom Prospective Diabetes Study Outcomes Model v2.01. We analyzed the trial as a 2 × 2 factorial trial (ignoring interactions between action-planning leaflet and medication), as a 2 × 2 × 2 factorial trial (considering all interactions), and ignoring all interactions. RESULTS: We observed several qualitative interactions for costs and quality-adjusted life-years (QALYs) that changed treatment rankings. However, different approaches to analyzing the factorial design did not change the conclusions. There was a ≥99% chance that atorvastatin is cost-effective and omega-3 is not, at a £20 000/QALY threshold. CONCLUSIONS: Atorvastatin monotherapy was the most cost-effective combination of the 3 trial interventions at a £20 000/QALY threshold. Omega-3 fish oil was not cost-effective, while there was insufficient evidence to draw firm conclusions about action planning. Recently-developed methods for analyzing factorial trials and combining parameter and sampling uncertainty were extended to estimate cost-effectiveness acceptability curves within a 2x2x2 factorial design with model-based extrapolation.

Which interactions matter in economic evaluations? A systematic review and simulation study.

BACKGROUND: We aimed to assess the magnitude of interactions in costs, quality-adjusted life-years (QALYs) and net benefits within a sample of published economic evaluations of factorial randomised controlled trials (RCTs), evaluate the impact that different analytical methods would have had on the results and compare the performance of different criteria for identifying which interactions should be taken into account. METHODS: We conducted a systematic review of full economic evaluations conducted alongside factorial RCTs and reviewed the methods used in different studies, as well as the incidence, magnitude, statistical significance, and type of interactions observed within the trials. We developed the interaction-effect ratio as a measure of the magnitude of interactions relative to main effects. For those studies reporting sufficient data, we assessed whether changing the form of analysis to ignore or include interactions would have changed the conclusions. We evaluated how well different criteria for identifying which interactions should be taken into account in the analysis would perform in practice, using simulated data generated to match the summary statistics of the studies identified in the review. RESULTS: Large interactions for economic endpoints occurred frequently within the 40 studies identified in the review, although interactions rarely changed the conclusions. CONCLUSIONS: Simulation work demonstrated that in analyses of factorial RCTs, taking account of all interactions or including interactions above a certain size (regardless of statistical significance) minimised the opportunity cost from adopting treatments that do not in fact have the highest true net benefit.

Is stratification testing for treatment of chronic obstructive pulmonary disease exacerbations cost-effective in primary care? an early cost-utility analysis.

OBJECTIVES: Patients with chronic obstructive pulmonary disease (COPD) who experience acute exacerbations usually require treatment with oral steroids or antibiotics, depending on the etiology of the exacerbation. Current management is based on clinician's assessment and judgement, which lacks diagnostic accuracy and results in overtreatment. A test to guide these decisions in primary care is in development. We developed an early decision model to evaluate the cost-effectiveness of this treatment stratification test in the primary care setting in the United Kingdom. METHODS: A combined decision tree and Markov model was developed of COPD progression and the exacerbation care pathway. Sensitivity analysis was carried out to guide technology development and inform evidence generation requirements. RESULTS: The base case test strategy cost GBP 423 (USD 542) less and resulted in a health gain of 0.15 quality-adjusted life-years per patient compared with not testing. Testing reduced antibiotic prescriptions by 30 percent, potentially lowering the risk of antimicrobial resistance developing. In sensitivity analysis, the result depended on the clinical effects of treating patients according to the test result, as opposed to treating according to clinical judgement alone, for which there is limited evidence. The results were less sensitive to the accuracy of the test. CONCLUSIONS: Testing may be cost-saving in primary care, but this requires robust evidence on whether test-guided treatment is effective. High quality evidence on the clinical utility of testing is required for early modeling of diagnostic tests generally.

Cooled radiofrequency ablation of the genicular nerves for chronic pain due to osteoarthritis of the knee: a cost-effectiveness analysis based on trial data.

BACKGROUND: For patients with painful knee osteoarthritis, long-term symptomatic relief may improve quality of life. Cooled radiofrequency ablation (CRFA) has demonstrated significant improvements in pain, physical function and health-related quality of life compared with conservative therapy with intra-articular steroid (IAS) injections. This study aimed to establish the cost-effectiveness of CRFA compared with IAS for managing moderate to severe osteoarthritis-related knee pain, from the US Medicare system perspective. METHODS: We conducted a cost-effectiveness analysis utilizing efficacy data (Oxford Knee Scores) from a randomized, crossover trial on CRFA (NCT02343003), which compared CRFA with IAS out to 6 and 12 months, and with IAS patients who subsequently crossed over to receive CRFA after 6 months. Outcomes included health benefits (quality-adjusted life-years [QALYs]), costs and cost-effectiveness (expressed as cost per QALY gained). QALYs were estimated by mapping Oxford Knee Scores to the EQ-5D generic utility measure using a validated algorithm. Secondary analyses explored differences in the settings of care and procedures used in-trial versus real-world clinical practice. RESULTS: CRFA resulted in an incremental QALY gain of 0.091 at an incremental cost of $1711, equating to a cost of US$18,773 per QALY gained over a 6-month time horizon versus IAS. Over a 12-month time horizon, the incremental QALY gain was 0.229 at the same incremental cost, equating to a cost of US$7462 per QALY gained versus IAS. Real-world cost assumptions resulted in modest increases in the cost per QALY gained to a maximum of US$21,166 and US$8296 at 6 and 12 months, respectively. Sensitivity analyses demonstrated that findings were robust to variations in efficacy and cost parameters. CONCLUSIONS: CRFA is a highly cost-effective treatment option for patients with osteoarthritis-related knee pain, compared with the US$100,000/QALY threshold typically used in the US.

Cost-effectiveness of replacing versus discarding the nail in children with nail bed injury.

Every year in the UK, around 10 000 children need to have operations to mend injuries to the bed of their fingernails. Currently, most children have their fingernail placed back on the injured nail bed after the operation. The NINJA trial found that children were slightly less likely to have an infection if the nail was thrown away rather than being put back, but the difference between groups was small and could have be due to chance. This study looked at whether replacing the nail is cost-effective compared with throwing it away. Using data from the NINJA trial, we compared costs, healthcare use, and quality of life and assessed the cost-effectiveness of replacing the nail. It was found that throwing the nail away after surgery would save the National Health Service (NHS) £75 (€85) per operation compared with placing the nail back on the nail bed. Changing clinical practice could save the NHS in England £720 000 (€819 000) per year.

Review and critical appraisal of studies mapping from quality of life or clinical measures to EQ-5D: an online database and application of the MAPS statement.

BACKGROUND: The Health Economics Research Centre (HERC) Database of Mapping Studies was established in 2013, based on a systematic review of studies developing mapping algorithms predicting EQ-5D. The Mapping onto Preference-based measures reporting Standards (MAPS) statement was published in 2015 to improve reporting of mapping studies. We aimed to update the systematic review and assess the extent to which recently-published studies mapping condition-specific quality of life or clinical measures to the EQ-5D follow the guidelines published in the MAPS Reporting Statement. METHODS: A published systematic review was updated using the original inclusion criteria to include studies published by December 2016. We included studies reporting novel algorithms mapping from any clinical measure or patient-reported quality of life measure to either the EQ-5D-3L or EQ-5D-5L. Titles and abstracts of all identified studies and the full text of papers published in 2016 were assessed against the MAPS checklist. RESULTS: The systematic review identified 144 mapping studies reporting 190 algorithms mapping from 110 different source instruments to EQ-5D. Of the 17 studies published in 2016, nine (53%) had titles that followed the MAPS statement guidance, although only two (12%) had abstracts that fully addressed all MAPS items. When the full text of these papers was assessed against the complete MAPS checklist, only two studies (12%) were found to fulfil or partly fulfil all criteria. Of the 141 papers (across all years) that included abstracts, the items on the MAPS statement checklist that were fulfilled by the largest number of studies comprised having a structured abstract (95%) and describing target instruments (91%) and source instruments (88%). CONCLUSIONS: The number of published mapping studies continues to increase. Our updated database provides a convenient way to identify mapping studies for use in cost-utility analysis. Most recent studies do not fully address all items on the MAPS checklist.

Economic evaluation of factorial randomised controlled trials: challenges, methods and recommendations.

Increasing numbers of economic evaluations are conducted alongside randomised controlled trials. Such studies include factorial trials, which randomise patients to different levels of two or more factors and can therefore evaluate the effect of multiple treatments alone and in combination. Factorial trials can provide increased statistical power or assess interactions between treatments, but raise additional challenges for trial-based economic evaluations: interactions may occur more commonly for costs and quality-adjusted life-years (QALYs) than for clinical endpoints; economic endpoints raise challenges for transformation and regression analysis; and both factors must be considered simultaneously to assess which treatment combination represents best value for money. This article aims to examine issues associated with factorial trials that include assessment of costs and/or cost-effectiveness, describe the methods that can be used to analyse such studies and make recommendations for health economists, statisticians and trialists. A hypothetical worked example is used to illustrate the challenges and demonstrate ways in which economic evaluations of factorial trials may be conducted, and how these methods affect the results and conclusions. Ignoring interactions introduces bias that could result in adopting a treatment that does not make best use of healthcare resources, while considering all interactions avoids bias but reduces statistical power. We also introduce the concept of the opportunity cost of ignoring interactions as a measure of the bias introduced by not taking account of all interactions. We conclude by offering recommendations for planning, analysing and reporting economic evaluations based on factorial trials, taking increased analysis costs into account. © 2017 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.

Generic and disease-specific estimates of quality of life in macular degeneration: mapping the MacDQoL onto the EQ-5D-3L.

PURPOSE: The macular degeneration quality of life (MacDQoL) instrument is a validated condition-specific measure of quality of life in patients with macular degeneration. This paper presents the first mapping algorithm to predict EQ-5D from responses to the MacDQoL instrument. METHODS: Responses to the MacDQoL and EQ-5D-3L instruments from 482 patients were collected from the IVAN multicentre trial of two alternative drug treatments for neovascular age-related macular degeneration. Regression specifications were estimated using OLS, censored least absolute deviation, Tobit and two-part models. Their predictive performance was assessed using mean squared error. An internal validation sample based on a random selection of 25 % of patients was used to assess the performance of the model estimated on the remaining 75 % of patients. RESULTS: A two-part model had the best predictive performance on the full sample. The covariates of this model include responses and weighted impact scores for all 23 condition-specific domains of the MacDQoL, and responses to a general MacDQoL quality of life question. The selected models were successful at predicting means and standard deviations of target populations, but prediction is weaker at the upper and lower extremes of the EQ-5D-3L distribution. CONCLUSION: The mapping algorithms provide a means of predicting EQ-5D-3L index scores from MacDQoL scores, and could facilitate cost-effectiveness analyses when the latter but not the former are available to researchers. Further validation of the performance of the algorithms using external data would provide a means of establishing the robustness of the algorithms.

Preferred reporting items for studies mapping onto preference-based outcome measures: the MAPS statement.

BACKGROUND AND AIM: 'Mapping' onto generic preference-based outcome measures is increasingly being used as a means of generating health utilities for use within health economic evaluations. Despite publication of technical guides for the conduct of mapping research, guidance for the reporting of mapping studies is currently lacking. The MApping onto Preference-based measures reporting Standards (MAPS) statement is a new checklist, which aims to promote complete and transparent reporting of mapping studies. METHODS: In the absence of previously published reporting checklists or reporting guidance documents, a de novo list of reporting items was created by a working group comprised of six health economists and one Delphi methodologist. A two-round, modified Delphi survey with representatives from academia, consultancy, health technology assessment agencies and the biomedical journal editorial community was used to identify a list of essential reporting items from this larger list. RESULTS: From the initial de novo list of 29 candidate items, a set of 23 essential reporting items was developed. The items are presented numerically and categorised within six sections, namely (1) title and abstract; (2) introduction; (3) methods; (4) results; (5) discussion; and (6) other. The MAPS statement is best applied in conjunction with the accompanying MAPS explanation and elaboration document. CONCLUSIONS: It is anticipated that the MAPS statement will improve the clarity, transparency and completeness of reporting of mapping studies. To facilitate dissemination and uptake, the MAPS statement is being co-published by seven health economics and quality of life journals, and broader endorsement is encouraged. The MAPS working group plans to assess the need for an update of the reporting checklist in 5 years' time.

Preferred reporting items for studies mapping onto preference-based outcome measures: The MAPS statement.

'Mapping' onto generic preference-based outcome measures is increasingly being used as a means of generating health utilities for use within health economic evaluations. Despite publication of technical guides for the conduct of mapping research, guidance for the reporting of mapping studies is currently lacking. The MAPS (MApping onto Preference-based measures reporting Standards) statement is a new checklist, which aims to promote complete and transparent reporting of mapping studies. The primary audiences for the MAPS statement are researchers reporting mapping studies, the funders of the research, and peer reviewers and editors involved in assessing mapping studies for publication.A de novo list of 29 candidate reporting items and accompanying explanations was created by a working group comprised of six health economists and one Delphi methodologist. Following a two-round, modified Delphi survey with representatives from academia, consultancy, health technology assessment agencies and the biomedical journal editorial community, a final set of 23 items deemed essential for transparent reporting, and accompanying explanations, was developed. The items are contained in a user friendly 23 item checklist. They are presented numerically and categorised within six sections, namely: (i) title and abstract; (ii) introduction; (iii) methods; (iv) results; (v) discussion; and (vi) other. The MAPS statement is best applied in conjunction with the accompanying MAPS explanation and elaboration document.It is anticipated that the MAPS statement will improve the clarity, transparency and completeness of reporting of mapping studies. To facilitate dissemination and uptake, the MAPS statement is being co-published by eight health economics and quality of life journals, and broader endorsement is encouraged. The MAPS working group plans to assess the need for an update of the reporting checklist in five years' time.This statement was published jointly in Applied Health Economics and Health Policy, Health and Quality of Life Outcomes, International Journal of Technology Assessment in Health Care, Journal of Medical Economics, Medical Decision Making, PharmacoEconomics, and Quality of Life Research.

The Influence of Cost-Effectiveness and Other Factors on Nice Decisions.

The National Institute for Health and Care Excellence (NICE) emphasises that cost-effectiveness is not the only consideration in health technology appraisal and is increasingly explicit about other factors considered relevant but not the weight attached to each. The objective of this study is to investigate the influence of cost-effectiveness and other factors on NICE decisions and whether NICE's decision-making has changed over time. We model NICE's decisions as binary choices for or against a health care technology in a specific patient group. Independent variables comprised of the following: clinical and economic evidence; characteristics of patients, disease or treatment; and contextual factors potentially affecting decision-making. Data on all NICE decisions published by December 2011 were obtained from HTAinSite [www.htainsite.com]. Cost-effectiveness alone correctly predicted 82% of decisions; few other variables were significant and alternative model specifications had similar performance. There was no evidence that the threshold has changed significantly over time. The model with highest prediction accuracy suggested that technologies costing £40 000 per quality-adjusted life-year (QALY) have a 50% chance of NICE rejection (75% at £52 000/QALY; 25% at £27 000/QALY). Past NICE decisions appear to have been based on a higher threshold than £20 000-£30 000/QALY. However, this may reflect consideration of other factors that cannot be easily quantified. © 2014 The Authors. Health Economics published by John Wiley & Sons Ltd.

PREFERRED REPORTING ITEMS FOR STUDIES MAPPING ONTO PREFERENCE-BASED OUTCOME MEASURES: THE MAPS STATEMENT.

BACKGROUND: "Mapping" onto generic preference-based outcome measures is increasingly being used as a means of generating health utilities for use within health economic evaluations. Despite publication of technical guides for the conduct of mapping research, guidance for the reporting of mapping studies is currently lacking. The MAPS (MApping onto Preference-based measures reporting Standards) statement is a new checklist, which aims to promote complete and transparent reporting of mapping studies. METHODS: In the absence of previously published reporting checklists or reporting guidance documents, a de novo list of reporting items was created by a working group comprised of six health economists and one Delphi methodologist. A two-round, modified Delphi survey with representatives from academia, consultancy, health technology assessment agencies, and the biomedical journal editorial community was used to identify a list of essential reporting items from this larger list. RESULTS: From the initial de novo list of twenty-nine candidate items, a set of twenty-three essential reporting items was developed. The items are presented numerically and categorized within six sections, namely: (i) title and abstract, (ii) introduction, (iii) methods, (iv) results, (v) discussion, and (vi) other. The MAPS statement is best applied in conjunction with the accompanying MAPS explanation and elaboration document. CONCLUSIONS: It is anticipated that the MAPS statement will improve the clarity, transparency. and completeness of reporting of mapping studies. To facilitate dissemination and uptake, the MAPS statement is being co-published by seven health economics and quality of life journals, and broader endorsement is encouraged. The MAPS working group plans to assess the need for an update of the reporting checklist in five years' time.

Rationing in an Era of Multiple Tight Constraints: Is Cost-Utility Analysis Still Fit for Purpose?

Cost-utility analysis may not be sufficient to support reimbursement decisions when the assessed health intervention requires a large proportion of the healthcare budget or when the monetary healthcare budget is not the only resource constraint. Such cases include joint replacement, coronavirus disease 2019 (COVID-19) interventions and settings where all resources are constrained (e.g. post-COVID-19 or in low/middle-income countries). Using literature on health technology assessment, rationing and reimbursement in healthcare, we identified seven alternative frameworks for simultaneous decisions about (dis)investment and proposed modifications to deal with multiple resource constraints. These frameworks comprised constrained optimisation; cost-effectiveness league table; 'step-in-the-right-direction' approach; heuristics based on effective gradients; weighted cost-effectiveness ratios; multicriteria decision analysis (MCDA); and programme budgeting and marginal analysis (PBMA). We used numerical examples to demonstrate how five of these alternative frameworks would operate. The modified frameworks we propose could be used in local commissioning and/or health technology assessment to supplement standard cost-utility analysis for interventions that have large budget impact and/or are subject to additional constraints.

Estimating Risk Factor Time Paths Among People with Type 2 Diabetes and QALY Gains from Risk Factor Management.

OBJECTIVES: Most type 2 diabetes simulation models utilise equations mapping out lifetime trajectories of risk factors [e.g. glycated haemoglobin (HbA1c)]. Existing equations, using historic data or assuming constant risk factors, frequently underestimate or overestimate complication rates. Updated risk factor time path equations are needed for simulation models to more accurately predict complication rates. AIMS: (1) Update United Kingdom Prospective Diabetes Study Outcomes Model (UKPDS-OM2) risk factor time path equations; (2) compare quality-adjusted life-years (QALYs) using original and updated equations; and (3) compare QALY gains for reference case simulations using different risk factor equations. METHODS: Using pooled contemporary data from two randomised trials EXSCEL and TECOS (n = 28,608), we estimated: dynamic panel models of seven continuous risk factors (high-density lipoprotein cholesterol, low density lipoprotein cholesterol, HbA1c, haemoglobin, heart rate, blood pressure and body mass index); two-step models of estimated glomerular filtration rate; and survival analyses of peripheral arterial disease, atrial fibrillation and albuminuria. UKPDS-OM2-derived lifetime QALYs were extrapolated over 70 years using historical and the new risk factor equations. RESULTS: All new risk factor equation predictions were within 95% confidence intervals of observed values, displaying good agreement between observed and estimated values. Historical risk factor time path equations predicted trial participants would accrue 9.84 QALYs, increasing to 10.98 QALYs using contemporary equations. DISCUSSION: Incorporating updated risk factor time path equations into diabetes simulation models could give more accurate predictions of long-term health, costs, QALYs and cost-effectiveness estimates, as well as a more precise understanding of the impact of diabetes on patients' health, expenditure and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT01144338 and NCT00790205.

Using orthopaedic health care resources efficiently: A cost analysis of day surgery for unicompartmental knee replacement.

BACKGROUND: Day surgery for unicompartmental knee replacement (UKR) could potentially reduce hospital costs. We aimed to measure the impact of introducing a day surgery UKR pathway on mean length of stay (LOS) and costs for the UK NHS, compared to an accelerated inpatient pathway. Secondly, the study aimed to compare the magnitude of costs using three costing approaches: top-down costing; simple micro-costing; and real-world costing. METHODS: We conducted an observational, before-and-after study of 2,111 UKR patients at one NHS hospital: 1,094 patients followed the day surgery pathway between September 2017 and February 2020; and 1,017 patients followed the accelerated inpatient pathway between September 2013 and February 2016. Top-down costs were estimated using Average NHS Costs. Simple micro-costing used the cost per bed-day. Real-world costs for this centre were estimated by costing actual changes in staffing levels. RESULTS: 532 (48.5%) patients in the day surgery pathway were discharged on the day of surgery compared with 36 (3.5%) patients in the accelerated inpatient pathway. The day surgery pathway reduced the mean LOS by 2.2 (95% CI: 1.81, 2.53) nights and was associated with an 18% decrease in Average NHS Costs (p < 0.001). Mean savings were £1,429 per patient with the Average NHS Costs approach, £905 per patient with the micro-costing approach, and £577 per patient with the "real-world" costing approach. Overall, moving NHS UKR surgeries to a day surgery pathway could save the NHS £8,659,740 per year. CONCLUSION: Day surgery for UKR could produce substantial cost savings for hospitals and the NHS.

Health poverty among people with type 2 diabetes mellitus (T2DM) in Malaysia.

In the context of the escalating burden of diabetes in low and middle-income countries (LMICs), there is a pressing concern about the widening disparities in care and outcomes across socioeconomic groups. This paper estimates health poverty measures among individuals with type 2 diabetes mellitus (T2DM) in Malaysia. Using data from the National Diabetes Registry between 2009 and 2018, the study linked 932,855 people with T2DM aged 40-75 to death records. Cox proportional hazards models were used to estimate the 5-year survival probabilities for each patient, stratified by age and sex, while controlling for comorbidities and area-based indicators of socio-economic status (SES), such as district-level asset-based indices and night-time luminosity. Measures of health poverty, based on the Foster-Greer-Thorbecke (FGT) measures, were employed to capture excessive risk of premature mortality. Two poverty line thresholds were used, namely a 5% and 10% reduction in survival probability compared to age and sex-adjusted survival probability of the general population. Counterfactual simulations estimated the extent to which comorbidities contribute to health poverty. 43.5% of the sample experienced health poverty using the 5% threshold, and 8.9% were health poor using the 10% threshold. Comorbidities contribute 2.9% for males and 5.4% for females, at the 5% threshold. At the 10% threshold, they contribute 7.4% for males and 3.4% for females. If all patients lived in areas of highest night-light intensity, poverty would fall by 5.8% for males and 4.6% for females at the 5% threshold, and 4.1% for males and 0.8% for females at the 10% threshold. In Malaysia, there is a high incidence of health poverty among people with diabetes, and it is strongly associated with comorbidities and area-based measures of SES. Expanding the application of health poverty measurement, through a combination of clinical registries and open spatial data, can facilitate simulations for health poverty alleviation.

Co-aggregation with Apolipoprotein E modulates the function of Amyloid-ß in Alzheimer's disease.

Which isoforms of apolipoprotein E (apoE) we inherit determine our risk of developing late-onset Alzheimer's Disease (AD), but the mechanism underlying this link is poorly understood. In particular, the relevance of direct interactions between apoE and amyloid-ß (Aß) remains controversial. Here, single-molecule imaging shows that all isoforms of apoE associate with Aß in the early stages of aggregation and then fall away as fibrillation happens. ApoE-Aß co-aggregates account for ~50% of the mass of diffusible Aß aggregates detected in the frontal cortices of homozygotes with the higher-risk APOE4 gene. We show how dynamic interactions between apoE and Aß tune disease-related functions of Aß aggregates throughout the course of aggregation. Our results connect inherited APOE genotype with the risk of developing AD by demonstrating how, in an isoform- and lipidation-specific way, apoE modulates the aggregation, clearance and toxicity of Aß. Selectively removing non-lipidated apoE4-Aß co-aggregates enhances clearance of toxic Aß by glial cells, and reduces secretion of inflammatory markers and membrane damage, demonstrating a clear path to AD therapeutics.