Self-managed, computerised word finding therapy as an add-on to usual care for chronic aphasia post-stroke: An economic evaluation.

OBJECTIVE: To examine the cost-effectiveness of self-managed computerised word finding therapy as an add-on to usual care for people with aphasia post-stroke. DESIGN: Cost-effectiveness modelling over a life-time period, taking a UK National Health Service (NHS) and personal social service perspective. SETTING: Based on the Big CACTUS randomised controlled trial, conducted in 21 UK NHS speech and language therapy departments. PARTICIPANTS: Big CACTUS included 278 people with long-standing aphasia post-stroke. INTERVENTIONS: Computerised word finding therapy plus usual care; usual care alone; usual care plus attention control. MAIN MEASURES: Incremental cost-effectiveness ratios (ICER) were calculated, comparing the cost per quality adjusted life year (QALY) gained for each intervention. Credible intervals (CrI) for costs and QALYs, and probabilities of cost-effectiveness, were obtained using probabilistic sensitivity analysis. Subgroup and scenario analyses investigated cost-effectiveness in different subsets of the population, and the sensitivity of results to key model inputs. RESULTS: Adding computerised word finding therapy to usual care had an ICER of £42,686 per QALY gained compared with usual care alone (incremental QALY gain: 0.02 per patient (95% CrI: -0.05 to 0.10); incremental costs: £732.73 per patient (95% CrI: £674.23 to £798.05)). ICERs for subgroups with mild or moderate word finding difficulties were £22,371 and £21,262 per QALY gained respectively. CONCLUSION: Computerised word finding therapy represents a low cost add-on to usual care, but QALY gains and estimates of cost-effectiveness are uncertain. Computerised therapy is more likely to be cost-effective for people with mild or moderate, as opposed to severe, word finding difficulties.

Mapping From Visual Acuity to EQ-5D, EQ-5D With Vision Bolt-On, and VFQ-UI in Patients With Macular Edema in the LEAVO Trial.

OBJECTIVES: Mappings to convert clinical measures to preference-based measures of health such as the EQ-5D-3L are sometimes required in cost-utility analyses. We developed mappings to convert best-corrected visual acuity (BCVA) to the EQ-5D-3L, the EQ-5D-3L with a vision bolt-on (EQ-5D V), and the Visual Functioning Questionnaire-Utility Index (VFQ-UI) in patients with macular edema caused by central retinal vein occlusion. METHODS: We used data from Lucentis, Eylea, Avastin in vein occlusion (LEAVO), which is a phase-3 randomized controlled trial comparing ranibizumab, aflibercept, and bevacizumab in 463 patients with observations at 6 time points. We estimated adjusted limited dependent variable mixture models consisting of 1 to 4 distributions (components) using BCVA in each eye, age, and sex to predict utility within the components and BCVA as a determinant of component membership. We compared model fit using mean error, mean absolute error, root mean square error, Akaike information criteria, Bayesian information criteria, and visual inspection of mean predicted and observed utilities and cumulative distribution functions. RESULTS: Mean utility scores were 0.82 for the EQ-5D-3L, 0.79 for the EQ-5D V, and 0.88 for the VFQ-UI. The best-fitting models for the EQ-5D and EQ-5D V had 2 components (with means of approximately 0.44 and 0.85), and the best-fitting model for VFQ-UI had 3 components (with means of approximately 0.95, 0.74, and 0.90). CONCLUSIONS: Models with multiple components better predict utility than those with single components. This article provides a valuable addition to the literature, in which previous mappings in visual acuity have been limited to linear regressions, resulting in unfounded assumptions about the distribution of the dependent variable.

The impact of an intervention to increase uptake to structured self-management education for people with type 2 diabetes mellitus in primary care (the embedding package), compared to usual care, on glycaemic control: study protocol for a mixed methods study incorporating a wait-list cluster randomised controlled trial.

BACKGROUND: Approximately 425 million people globally have diabetes, with ~ 90% of these having Type 2 Diabetes Mellitus (T2DM). This is a condition that leads to a poor quality of life and increased risk of serious health complications. Structured self-management education (SSME) has been shown to be effective in improving glycaemic control and patient related outcome measures and to be cost-effective. However, despite the demonstrated benefits, attendance at SSME remains low. An intervention has been developed to embed SSME called the 'Embedding Package'. The intervention aims to address barriers and enhance enablers to uptake of SSME at patient, healthcare professional and organisational levels. It comprises a marketing strategy, user friendly and effective referral pathways, new roles to champion SSME and a toolkit of resources. METHODS: A mixed methods study incorporating a wait-list cluster randomised trial and ethnographic study, including 66 UK general practices, will be conducted with two intervention start times (at 0 and 9 months), each followed by an active delivery phase. At 18 months, the intervention will cease to be actively delivered and a 12 month observational follow-up phase will begin. The intervention, the Embedding Package, aims to increase SSME uptake and subsequent improvements in health outcomes, through a clear marketing strategy, user friendly and effective referral pathways, a local clinical champion and an 'Embedder' and a toolkit of resources for patients, healthcare professionals and other key stakeholders. The primary aim is, through increasing uptake to and attendance at SSME, to reduce HbA1c in people with T2DM compared with usual care. Secondary objectives include: assessing whether there is an increase in referral to and uptake of SSME and improvements in biomedical and psychosocial outcomes; an assessment of the sustainability of the Embedding Package; contextualising the process of implementation, sustainability of change and the 'fit' of the Embedding Package; and an assessment of the cost-effectiveness of the Embedding Package. DISCUSSION: This study will assess the effectiveness, cost-effectiveness and sustainability of the Embedding Package, an intervention which aims to improve biomedical and psychosocial outcomes of people with T2DM, through increased referral to and uptake of SSME. TRIAL REGISTRATION: International Standard Randomised Controlled Trials Number ISRCTN23474120. Assigned 05/04/2018. The study was prospectively registered. On submission of this manuscript practice recruitment is complete, participant recruitment is ongoing and expected to be completed by the end of 2019.

Haemorrhoidal artery ligation versus rubber band ligation for the management of symptomatic second-degree and third-degree haemorrhoids (HubBLe): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Optimum surgical intervention for low-grade haemorrhoids is unknown. Haemorrhoidal artery ligation (HAL) has been proposed as an efficacious, safe therapy while rubber band ligation (RBL) is a commonly used outpatient treatment. We compared recurrence after HAL versus RBL in patients with grade II-III haemorrhoids. METHODS: This multicentre, open-label, parallel group, randomised controlled trial included patients from 17 acute UK NHS trusts. We screened patients aged 18 years or older presenting with grade II-III haemorrhoids. We excluded patients who had previously received any haemorrhoid surgery, more than one injection treatment for haemorrhoids, or more than one RBL procedure within 3 years before recruitment. Eligible patients were randomly assigned (in a 1:1 ratio) to either RBL or HAL with Doppler. Randomisation was computer-generated and stratified by centre with blocks of random sizes. Allocation concealment was achieved using a web-based system. The study was open-label with no masking of participants, clinicians, or research staff. The primary outcome was recurrence at 1 year, derived from the patient's self-reported assessment in combination with resource use from their general practitioner and hospital records. Recurrence was analysed in patients who had undergone one of the interventions and been followed up for at least 1 year. This study is registered with the ISRCTN registry, ISRCTN41394716. FINDINGS: From Sept 9, 2012, to May 6, 2014, of 969 patients screened, 185 were randomly assigned to the HAL group and 187 to the RBL group. Of these participants, 337 had primary outcome data (176 in the RBL group and 161 in the HAL group). At 1 year post-procedure, 87 (49%) of 176 patients in the RBL group and 48 (30%) of 161 patients in the HAL group had haemorrhoid recurrence (adjusted odds ratio [aOR] 2·23, 95% CI 1·42-3·51; p=0·0005). The main reason for this difference was the number of extra procedures required to achieve improvement (57 [32%] participants in the RBL group and 23 [14%] participants in the HAL group had a subsequent procedure for haemorrhoids). The mean pain 1 day after procedure was 3·4 (SD 2·8) in the RBL group and 4·6 (2·8) in the HAL group (difference -1·2, 95% CI -1·8 to -0·5; p=0·0002); at day 7 the scores were 1·6 (2·3) in the RBL group and 3·1 (2·4) in the HAL group (difference -1·5, -2·0 to -1·0; p<0·0001). Pain scores did not differ between groups at 21 days and 6 weeks. 15 individuals reported serious adverse events requiring hospital admission. One patient in the RBL group had a pre-existing rectal tumour. Of the remaining 14 serious adverse events, 12 (7%) were among participants treated with HAL and two (1%) were in those treated with RBL. Six patients had pain (one treated with RBL, five treated with HAL), three had bleeding not requiring transfusion (one treated with RBL, two treated with HAL), two in the HAL group had urinary retention, two in the HAL group had vasovagal upset, and one in the HAL group had possible sepsis (treated with antibiotics). INTERPRETATION: Although recurrence after HAL was lower than a single RBL, HAL was more painful than RBL. The difference in recurrence was due to the need for repeat bandings in the RBL group. Patients (and health commissioners) might prefer such a course of RBL to the more invasive HAL. FUNDING: NIHR Health Technology Assessment programme.

Cost Effectiveness of Ranibizumab vs Aflibercept vs Bevacizumab for the Treatment of Macular Oedema Due to Central Retinal Vein Occlusion: The LEAVO Study.

BACKGROUND: We aimed to assess the cost effectiveness of intravitreal ranibizumab (Lucentis), aflibercept (Eylea) and bevacizumab (Avastin) for the treatment of macular oedema due to central retinal vein occlusion. METHODS: We calculated costs and quality-adjusted life-years from the UK National Health Service and Personal Social Services perspective. We performed a within-trial analysis using the efficacy, safety, resource use and health utility data from a randomised controlled trial (LEAVO) over 100 weeks. We built a discrete event simulation to model long-term outcomes. We estimated utilities using the Visual-Functioning Questionnaire-Utility Index, EQ-5D and EQ-5D with an additional vision question. We used standard UK costs sources for 2018/19 and a cost of £28 per bevacizumab injection. We discounted costs and quality-adjusted life-years at 3.5% annually. RESULTS: Bevacizumab was the least costly intervention followed by ranibizumab and aflibercept in both the within-trial analysis (bevacizumab: £6292, ranibizumab: £13,014, aflibercept: £14,328) and long-term model (bevacizumab: £18,353, ranibizumab: £30,226, aflibercept: £35,026). Although LEAVO did not demonstrate bevacizumab to be non-inferior for the visual acuity primary outcome, the three interventions generated similar quality-adjusted life-years in both analyses. Bevacizumab was always the most cost-effective intervention at a threshold of £30,000 per quality-adjusted life-year, even using the list price of £243 per injection. CONCLUSIONS: Wider adoption of bevacizumab for the treatment of macular oedema due to central retinal vein occlusion could result in substantial savings to healthcare systems and deliver similar health-related quality of life. However, patients, funders and ophthalmologists should be fully aware that LEAVO could not demonstrate that bevacizumab is non-inferior to the licensed agents.

Intravitreal ranibizumab versus aflibercept versus bevacizumab for macular oedema due to central retinal vein occlusion: the LEAVO non-inferiority three-arm RCT.

BACKGROUND: Licensed ranibizumab (0.5 mg/0.05 ml Lucentis®; Novartis International AG, Basel, Switzerland) and aflibercept (2 mg/0.05 ml Eylea®; Bayer AG, Leverkusen, Germany) and unlicensed bevacizumab (1.25 mg/0.05 ml Avastin®; F. Hoffmann-La Roche AG, Basel, Switzerland) are used to treat macula oedema due to central retinal vein occlusion, but their relative clinical effectiveness, cost-effectiveness and impact on the UK NHS and Personal Social Services have never been directly compared over the typical disease treatment period. OBJECTIVE: The objective was to compare the clinical effectiveness and cost-effectiveness of three intravitreal antivascular endothelial growth factor agents for the management of macula oedema due to central retinal vein occlusion. DESIGN: This was a three-arm, double-masked, randomised controlled non-inferiority trial. SETTING: The trial was set in 44 UK NHS ophthalmology departments, between 2014 and 2018. PARTICIPANTS: A total of 463 patients with visual impairment due to macula oedema secondary to central retinal vein occlusion were included in the trial. INTERVENTIONS: The participants were treated with repeated intravitreal injections of ranibizumab (n = 155), aflibercept (n = 154) or bevacizumab (n = 154). MAIN OUTCOME MEASURES: The primary outcome was an increase in the best corrected visual acuity letter score from baseline to 100 weeks in the trial eye. The null hypothesis that aflibercept and bevacizumab are each inferior to ranibizumab was tested with a non-inferiority margin of -5 visual acuity letters over 100 weeks. Secondary outcomes included additional visual acuity, and imaging outcomes, Visual Function Questionnaire-25, EuroQol-5 Dimensions with and without a vision bolt-on, and drug side effects. Cost-effectiveness was estimated using treatment costs and Visual Function Questionnaire-Utility Index to measure quality-adjusted life-years. RESULTS: The adjusted mean changes at 100 weeks in the best corrected visual acuity letter scores were as follows - ranibizumab, 12.5 letters (standard deviation 21.1 letters); aflibercept, 15.1 letters (standard deviation 18.7 letters); and bevacizumab, 9.8 letters (standard deviation 21.4 letters). Aflibercept was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference 2.23 letters, 95% confidence interval -2.17 to 6.63 letters; p = 0.0006), but not superior. The study was unable to demonstrate that bevacizumab was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference -1.73 letters, 95% confidence interval -6.12 to 2.67 letters; p = 0.071). A post hoc analysis was unable to demonstrate that bevacizumab was non-inferior to aflibercept in the intention-to-treat population (adjusted mean best corrected visual acuity difference was -3.96 letters, 95% confidence interval -8.34 to 0.42 letters; p = 0.32). All per-protocol population results were the same. Fewer injections were required with aflibercept (10.0) than with ranibizumab (11.8) (difference in means -1.8, 95% confidence interval -2.9 to -0.8). A post hoc analysis showed that more bevacizumab than aflibercept injections were required (difference in means 1.6, 95% confidence interval 0.5 to 2.7). There were no new safety concerns. The model- and trial-based cost-effectiveness analyses estimated that bevacizumab was the most cost-effective treatment at a threshold of £20,000-30,000 per quality-adjusted life-year. LIMITATIONS: The comparison of aflibercept and bevacizumab was a post hoc analysis. CONCLUSION: The study showed aflibercept to be non-inferior to ranibizumab. However, the possibility that bevacizumab is worse than ranibizumab and aflibercept by 5 visual acuity letters cannot be ruled out. Bevacizumab is an economically attractive treatment alternative and would lead to substantial cost savings to the NHS and other health-care systems. However, uncertainty about its relative effectiveness should be discussed comprehensively with patients, their representatives and funders before treatment is considered. FUTURE WORK: To obtain extensive patient feedback and discuss with all stakeholders future bevacizumab NHS use. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13623634. 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. 25, No. 38. See the NIHR Journals Library website for further project information.

The eye functions like a camera. The retina, at the back of the eye, is the camera film, and the centre, the macula, allows us to see fine details. Approximately 6500 people each year in England and Wales are affected by fluid leaking out of congested tiny blood vessels, causing macular swelling or oedema. The cause is blockage of the main vein that normally drains blood from the retina. Three drugs, injected into the eye in tiny amounts every 4­8 weeks, have been shown to improve the vision of people with this condition. Two drugs, ranibizumab (0.5 mg/0.05 ml Lucentis^®; Novartis International AG, Basel, Switzerland) and aflibercept (2 mg/0.05 ml Eylea^®; Bayer AG, Leverkusen, Germany), are licensed for UK use, but the third, bevacizumab (1.25 mg/0.05 ml Avastin^®; F. Hoffmann-La Roche AG, Basel, Switzerland), is not, even though it is much cheaper and used extensively worldwide. To our knowledge, no trials have compared the three drugs over the typical 2-year treatment period. This multicentre, Phase III, double-masked, randomised controlled non-inferiority trial comparing the clinical effectiveness and cost-effectiveness of intravitreal therapy with ranibizumab (Lucentis) versus aflibercept (Eylea) versus bevacizumab (Avastin) for macular oedema due to central retinal Vein Occlusion (LEAVO) was designed to compare ranibizumab, aflibercept and bevacizumab in this type of macular oedema. The trial showed that all three drugs improved vision a lot, but bevacizumab improved vision to a slightly lesser degree than the other two drugs. All patients should be aware of these findings before considering their treatment options. A comparison of the costs and benefits of ranibizumab, aflibercept and bevacizumab, using data from the trial and other sources, found that all three led to similar improvements in quality of life. Because aflibercept and ranibizumab are so much more expensive, they may be poor value for money. If patients, their representatives and funders all agree, it may be possible to treat this type of macular oedema with bevacizumab, which is cheaper, keeping the other agents available if needed.

Computerised speech and language therapy or attention control added to usual care for people with long-term post-stroke aphasia: the Big CACTUS three-arm RCT.

BACKGROUND: People with aphasia may improve their communication with speech and language therapy many months/years after stroke. However, NHS speech and language therapy reduces in availability over time post stroke. OBJECTIVE: This trial evaluated the clinical effectiveness and cost-effectiveness of self-managed computerised speech and language therapy to provide additional therapy. DESIGN: A pragmatic, superiority, single-blind, parallel-group, individually randomised (stratified block randomisation, stratified by word-finding severity and site) adjunct trial. SETTING: Twenty-one UK NHS speech and language therapy departments. PARTICIPANTS: People with post-stroke aphasia (diagnosed by a speech and language therapist) with long-standing (> 4 months) word-finding difficulties. INTERVENTIONS: The groups were (1) usual care; (2) daily self-managed computerised word-finding therapy tailored by speech and language therapists and supported by volunteers/speech and language therapy assistants for 6 months plus usual care (computerised speech and language therapy); and (3) activity/attention control (completion of puzzles and receipt of telephone calls from a researcher for 6 months) plus usual care. MAIN OUTCOME MEASURES: Co-primary outcomes - change in ability to find treated words of personal relevance in a bespoke naming test (impairment) and change in functional communication in conversation rated on the activity scale of the Therapy Outcome Measures (activity) 6 months after randomisation. A key secondary outcome was participant-rated perception of communication and quality of life using the Communication Outcomes After Stroke questionnaire at 6 months. Outcomes were assessed by speech and language therapists using standardised procedures. Cost-effectiveness was estimated using treatment costs and an accessible EuroQol-5 Dimensions, five-level version, measuring quality-adjusted life-years. RESULTS: A total of 818 patients were assessed for eligibility and 278 participants were randomised between October 2014 and August 2016. A total of 240 participants (86 usual care, 83 computerised speech and language therapy, 71 attention control) contributed to modified intention-to-treat analysis at 6 months. The mean improvements in word-finding were 1.1% (standard deviation 11.2%) for usual care, 16.4% (standard deviation 15.3%) for computerised speech and language therapy and 2.4% (standard deviation 8.8%) for attention control. Computerised speech and language therapy improved word-finding 16.2% more than usual care did (95% confidence interval 12.7% to 19.6%; p < 0.0001) and 14.4% more than attention control did (95% confidence interval 10.8% to 18.1%). Most of this effect was maintained at 12 months (n = 219); the mean differences in change in word-finding score were 12.7% (95% confidence interval 8.7% to 16.7%) higher in the computerised speech and language therapy group (n = 74) than in the usual-care group (n = 84) and 9.3% (95% confidence interval 4.8% to 13.7%) higher in the computerised speech and language therapy group than in the attention control group (n = 61). Computerised speech and language therapy did not show significant improvements on the Therapy Outcome Measures or Communication Outcomes After Stroke scale compared with usual care or attention control. Primary cost-effectiveness analysis estimated an incremental cost per participant of £732.73 (95% credible interval £674.23 to £798.05). The incremental quality-adjusted life-year gain was 0.017 for computerised speech and language therapy compared with usual care, but its direction was uncertain (95% credible interval -0.05 to 0.10), resulting in an incremental cost-effectiveness ratio of £42,686 per quality-adjusted life-year gained. For mild and moderate word-finding difficulty subgroups, incremental cost-effectiveness ratios were £22,371 and £28,898 per quality-adjusted life-year gained, respectively, for computerised speech and language therapy compared with usual care. LIMITATIONS: This trial excluded non-English-language speakers, the accessible EuroQol-5 Dimensions, five-level version, was not validated and the measurement of attention control fidelity was limited. CONCLUSIONS: Computerised speech and language therapy enabled additional self-managed speech and language therapy, contributing to significant improvement in finding personally relevant words (as specifically targeted by computerised speech and language therapy) long term post stroke. Gains did not lead to improvements in conversation or quality of life. Cost-effectiveness is uncertain owing to uncertainty around the quality-adjusted life-year gain, but computerised speech and language therapy may be more cost-effective for participants with mild and moderate word-finding difficulties. Exploring ways of helping people with aphasia to use new words in functional communication contexts is a priority. TRIAL REGISTRATION: Current Controlled Trials ISRCTN68798818. 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. 24, No. 19. See the NIHR Journals Library website for further project information. The Tavistock Trust for Aphasia provided additional support to enable people in the control groups to experience the intervention after the trial had ended.

Aphasia is a communication disorder that can be caused by a stroke. It affects a person's understanding of spoken words and their talking, reading and writing abilities. Communication may improve months, or years, after a stroke with speech and language therapy. Many patients want more speech and language therapy than the NHS can provide. The Big CACTUS (clinical and cost-effectiveness of aphasia computer treatment versus usual stimulation or attention control long term post-stroke) trial evaluated the use of speech and language therapy software for people with aphasia to practise finding words independently at home on their own computer or one loaned by the NHS. People with aphasia who had had a stroke at least 4 months previously were randomly allocated to one of three groups: usual speech and language therapy caredaily use of computerised speech and language therapy for 6 months, tailored by a speech and language therapist and supported by a volunteer or speech and language therapy assistantdaily completion of puzzles and supportive telephone calls from a researcher to mimic the activity/attention the computerised speech and language therapy group received. All groups received usual speech and language therapy. A total of 278 people with aphasia took part in this trial, from 21 UK NHS speech and language therapy departments. They had their strokes between 4 months and 36 years previously. Computerised speech and language therapy enabled more practice (28 hours on average) than usual speech and language therapy (3.8 hours). The computerised speech and language therapy group significantly improved their ability to say words they chose to practise compared with those in the usual speech and language therapy or puzzle book groups. Although computerised speech and language therapy can help people with aphasia to learn new words for years after stroke, no improvements in conversation or quality of life were seen. The cost-effectiveness for the NHS is still uncertain. However, our best estimate is that it is unlikely to be cost-effective for everyone with aphasia, but it may be cost-effective for people with mild and moderate word-finding difficulties. Next steps will focus on how to encourage use of new words in conversation to have an impact on quality of life.

Increasing uptake of structured self-management education programmes for type 2 diabetes in a primary care setting: a feasibility study.

BACKGROUND: Structured self-management education (SSME) for people with type 2 diabetes mellitus (T2DM) improves biomedical and psychological outcomes, whilst being cost-effective. Yet uptake in the UK remains low. An 'Embedding Package' addressing barriers and enablers to uptake at patient, health care professional and organisational levels has been developed. The aim of this study was to test the feasibility of conducting a subsequent randomised controlled trial (RCT) to evaluate the Embedding Package in primary care, using a mixed methods approach. METHODS: A concurrent mixed methods approach was adopted. Six general practices in the UK were recruited and received the intervention (the Embedding Package). Pseudonymised demographic, biomedical and SSME data were extracted from primary care medical records for patients recorded as having a diagnosis of T2DM. Descriptive statistics assessed quantitative data completeness and accuracy. Quantitative data were supplemented and validated by a patient questionnaire, for which two recruitment methods were trialled. Where consent was given, the questionnaire and primary care data were linked and compared. The cost of the intervention was estimated. An integrated qualitative study comprising ethnography and stakeholder and patient interviews explored the process of implementation, sustainability of change and 'fit' of the intervention. Qualitative data were analysed using a thematic framework guided by the Normalisation Process Theory (NPT). RESULTS: Primary care data were extracted for 2877 patients. The primary outcome for the RCT, HbA1c, was over 90% complete. Questionnaires were received from 423 (14.7%) participants, with postal invitations yielding more participants than general practitioner (GP) prompts. Ninety-one percent of questionnaire participants consented to data linkage. The mean cost per patient for the Embedding Package was £8.94, over a median follow-up of 162.5 days. Removing the development cost, this reduces to £5.47 per patient. Adoption of ethnographic and interview methods in the collection of data was appropriate, and the use of NPT, whilst challenging, enhanced the understanding of the implementation process. The need to delay the collection of patient interview data to enable the intervention to inform patient care was highlighted. CONCLUSIONS: It is feasible to collect data with reasonable completeness and accuracy for the subsequent RCT, although refinement to improve the quality of the data collected will be undertaken. Based on resource use data collected, it was feasible to produce cost estimates for each individual component of the Embedding Package. The methods chosen to generate, collect and analyse qualitative data were satisfactory, keeping participant burden low and providing insight into potential refinements of the Embedding Package and customisation of the methods for the RCT. TRIAL REGISTRATION: ISRCTN, ISRCTN21321635, Registered 07/07/2017-retrospectively registered.

Statistical Methods for Adjusting Estimates of Treatment Effectiveness for Patient Nonadherence in the Context of Time-to-Event Outcomes and Health Technology Assessment: A Systematic Review of Methodological Papers.

Introduction. Medication nonadherence can have a significant negative impact on treatment effectiveness. Standard intention-to-treat analyses conducted alongside clinical trials do not make adjustments for nonadherence. Several methods have been developed that attempt to estimate what treatment effectiveness would have been in the absence of nonadherence. However, health technology assessment (HTA) needs to consider effectiveness under real-world conditions, where nonadherence levels typically differ from those observed in trials. With this analytical requirement in mind, we conducted a review to identify methods for adjusting estimates of treatment effectiveness in the presence of patient nonadherence to assess their suitability for use in HTA. Methods. A "Comprehensive Pearl Growing" technique, with citation searching and reference checking, was applied across 7 electronic databases to identify methodological papers for adjusting time-to-event outcomes for nonadherence using individual patient data. A narrative synthesis of identified methods was conducted. Methods were assessed in terms of their ability to reestimate effectiveness based on alternative, suboptimal adherence levels. Results. Twenty relevant methodological papers covering 12 methods and 8 extensions to those methods were identified. Methods are broadly classified into 4 groups: 1) simple methods, 2) principal stratification methods, 3) generalized methods (g-methods), and 4) pharmacometrics-based methods using pharmacokinetics and pharmacodynamics (PKPD) analysis. Each method makes specific assumptions and has associated limitations. Five of the 12 methods are capable of adjusting for real-world nonadherence, with only g-methods and PKPD considered appropriate for HTA. Conclusion. A range of statistical methods is available for adjusting estimates of treatment effectiveness for nonadherence, but most are not suitable for use in HTA. G-methods and PKPD appear to be more appropriate to estimate effectiveness in the presence of real-world adherence.

Self-managed, computerised speech and language therapy for patients with chronic aphasia post-stroke compared with usual care or attention control (Big CACTUS): a multicentre, single-blinded, randomised controlled trial.

BACKGROUND: Post-stroke aphasia might improve over many years with speech and language therapy; however speech and language therapy is often less readily available beyond a few months after stroke. We assessed self-managed computerised speech and language therapy (CSLT) as a means of providing more therapy than patients can access through usual care alone. METHODS: In this pragmatic, superiority, three-arm, individually randomised, single-blind, parallel group trial, patients were recruited from 21 speech and language therapy departments in the UK. Participants were aged 18 years or older and had been diagnosed with aphasia post-stroke at least 4 months before randomisation; they were excluded if they had another premorbid speech and language disorder caused by a neurological deficit other than stroke, required treatment in a language other than English, or if they were currently using computer-based word-finding speech therapy. Participants were randomly assigned (1:1:1) to either 6 months of usual care (usual care group), daily self-managed CSLT plus usual care (CSLT group), or attention control plus usual care (attention control group) with the use of computer-generated stratified blocked randomisation (randomly ordered blocks of sizes three and six, stratified by site and severity of word finding at baseline based on CAT Naming Objects test scores). Only the outcome assessors and trial statistician were masked to the treatment allocation. The speech and language therapists who were doing the outcome assessments were different from those informing participants about which group they were assigned to and from those delivering all interventions. The statistician responsible for generating the randomisation schedule was separate from those doing the analysis. Co-primary outcomes were the change in ability to retrieve personally relevant words in a picture naming test (with 10% mean difference in change considered a priori as clinically meaningful) and the change in functional communication ability measured by masked ratings of video-recorded conversations, with the use of Therapy Outcome Measures (TOMs), between baseline and 6 months after randomisation (with a standardised mean difference in change of 0·45 considered a priori as clinically meaningful). Primary analysis was based on the modified intention-to-treat (mITT) population, which included randomly assigned patients who gave informed consent and excluded those without 6-month outcome measures. Safety analysis included all participants. This trial has been completed and was registered with the ISRCTN, number ISRCTN68798818. FINDINGS: From Oct 20, 2014, to Aug 18, 2016, 818 patients were assessed for eligibility, of which 278 (34%) participants were randomly assigned (101 [36%] to the usual care group; 97 [35%] to the CSLT group; 80 [29%] to the attention control group). 86 patients in the usual care group, 83 in the CSLT group, and 71 in the attention control group contributed to the mITT. Mean word finding improvements were 1·1% (SD 11·2) in the usual care group, 16·4% (15·3) in the CSLT group, and 2·4% (8·8) in the attention control group. Word finding improvement was 16·2% (95% CI 12·7 to 19·6; p<0·0001) higher in the CSLT group than in the usual care group and was 14·4% (10·8 to 18·1) higher than in the attention control group. Mean changes in TOMs were 0·05 (SD 0·59) in the usual care group (n=84), 0·04 (0·58) in the CSLT group (n=81), and 0·10 (0·61) in the attention control group (n=68); the mean difference in change between the CSLT and usual care groups was -0·03 (-0·21 to 0·14; p=0·709) and between the CSLT and attention control groups was -0·01 (-0·20 to 0·18). The incidence of serious adverse events per year were rare with 0·23 events in the usual care group, 0·11 in the CSLT group, and 0·16 in the attention control group. 40 (89%) of 45 serious adverse events were unrelated to trial activity and the remaining five (11%) of 45 serious adverse events were classified as unlikely to be related to trial activity. INTERPRETATION: CSLT plus usual care resulted in a clinically significant improvement in personally relevant word finding but did not result in an improvement in conversation. Future studies should explore ways to generalise new vocabulary to conversation for patients with chronic aphasia post-stroke. FUNDING: National Institute for Health Research, Tavistock Trust for Aphasia.

Cost-Effectiveness of Docetaxel and Paclitaxel for Adjuvant Treatment of Early Breast Cancer: Adaptation of a Model-Based Economic Evaluation From the United Kingdom to South Africa.

OBJECTIVES: Transferability of economic evaluations to low- and middle-income countries through adaptation of models is important; however, several methodological and practical challenges remain. Given its significant costs and the quality-of-life burden to patients, adjuvant treatment of early breast cancer was identified as a priority intervention by the South African National Department of Health. This study assessed the cost-effectiveness of docetaxel and paclitaxel-containing chemotherapy regimens (taxanes) compared with standard (non-taxane) treatments. METHODS: A cost-utility analysis was undertaken based on a UK 6-health-state Markov model adapted for South Africa using the Mullins checklist. The analysis assumed a 35-year time horizon. The model was populated with clinical effectiveness data (hazard ratios, recurrence rates, and adverse events) using direct comparisons from clinical trials. Resource use patterns and unit costs for estimating cost parameters (drugs, diagnostics, consumables, personnel) were obtained from South Africa. Uncertainty was assessed using probabilistic and deterministic sensitivity analyses. RESULTS: The incremental cost per patient for the docetaxel regimen compared with standard treatment was R6774. The incremental quality-adjusted life years (QALYs) were 0.24, generating an incremental cost-effectiveness ratio of R28430 per QALY. The cost of the paclitaxel regimen compared with standard treatment was estimated as -R578 and -R1512, producing an additional 0.03 and 0.025 QALYs, based on 2 trials. Paclitaxel, therefore, appears to be a dominant intervention. The base case results were robust to all sensitivity analyses. CONCLUSIONS: Based on the adapted model, docetaxel and paclitaxel are predicted to be cost-effective as adjuvant treatment for early breast cancer in South Africa.

Impact of pelvic floor muscle training on sexual function of women with urinary incontinence and a comparison of electrical stimulation versus standard treatment (IPSU trial): a randomised controlled trial.

AIMS: To evaluate the clinical and cost-effectiveness of electric stimulation plus standard pelvic floor muscle training compared to standard pelvic floor muscle training alone in women with urinary incontinence and sexual dysfunction. METHODS: Single centre two arm parallel group randomised controlled trial conducted in a Teaching hospital in England. Participants were women presenting with urinary incontinence and sexual dysfunction. The interventions compared were electric stimulation versus standard pelvic floor muscle training. OUTCOME MEASURES: included Prolapse and Incontinence Sexual function Questionnaire (PISQ) physical function dimension at post-treatment (primary); other dimensions of PISQ, SF-36; EQ-5D, EPAQ, resource use, adverse events and cost-effectiveness (secondary outcomes). RESULTS: 114 women were randomised (Intervention n=57; Control group n=57). 64/114 (56%). PARTICIPANTS: had valid primary outcome data at follow-up (Intervention 30; Control 34). The mean PISQ-PF dimension scores at follow-up were 33.1 (SD 5.5) and 32.3 (SD 5.2) for the Intervention and Control groups respectively; with the Control group having a higher (better) score. After adjusting for baseline score, BMI, menopausal status, time from randomisation and baseline oxford scale score the mean difference was -1.0 (95% CI: -4.0 to 1.9; P=0.474). There was no differences between the groups in any of the secondary outcomes at follow-up. Within this study, the use of electrical stimulation was cost-effective with very small incremental costs and quality adjusted life years (QALYs). CONCLUSIONS: In women presenting with urinary incontinence in conjunction with sexual dysfunction, physiotherapy is beneficial to improve overall sexual function. However no specific form of physiotherapy is beneficial over another. Trial registration ISRCTN09586238.

Cost-Effectiveness of Haemorrhoidal Artery Ligation versus Rubber Band Ligation for the Treatment of Grade II-III Haemorrhoids: Analysis Using Evidence from the HubBLe Trial.

AIM: Haemorrhoids are a common condition, with nearly 30,000 procedures carried out in England in 2014/15, and result in a significant quality-of-life burden to patients and a financial burden to the healthcare system. This study examined the cost effectiveness of haemorrhoidal artery ligation (HAL) compared with rubber band ligation (RBL) in the treatment of grade II-III haemorrhoids. METHOD: This analyses used data from the HubBLe study, a multicentre, open-label, parallel group, randomised controlled trial conducted in 17 acute UK hospitals between September 2012 and August 2015. A full economic evaluation, including long-term cost effectiveness, was conducted from the UK National Health Service (NHS) perspective. Main outcomes included healthcare costs, quality-adjusted life-years (QALYs) and recurrence. Cost-effectiveness results were presented in terms of incremental cost per QALY gained and cost per recurrence avoided. Extrapolation analysis for 3 years beyond the trial follow-up, two subgroup analyses (by grade of haemorrhoids and recurrence following RBL at baseline), and various sensitivity analyses were undertaken. RESULTS: In the primary base-case within-trial analysis, the incremental total mean cost per patient for HAL compared with RBL was £1027 (95% confidence interval [CI] £782-£1272, p < 0.001). The incremental QALYs were 0.01 QALYs (95% CI -0.02 to 0.04, p = 0.49). This generated an incremental cost-effectiveness ratio (ICER) of £104,427 per QALY. In the extrapolation analysis, the estimated probabilistic ICER was £21,798 per QALY. Results from all subgroup and sensitivity analyses did not materially change the base-case result. CONCLUSIONS: Under all assessed scenarios, the HAL procedure was not cost effective compared with RBL for the treatment of grade II-III haemorrhoids at a cost-effectiveness threshold of £20,000 per QALY; therefore, economically, its use in the NHS should be questioned.

Review of Economic Submissions to NICE Medical Technologies Evaluation Programme.

The economic evaluation of medical devices is increasingly used to inform decision making on adopting new or novel technologies; however, challenges are inevitable due to the unique characteristics of devices. Cost-consequence analyses are recommended and employed by the English National Institute for Health and Care Excellence (NICE) Medical Technologies Evaluation Programme (MTEP) to help address these challenges. The aim of this work was to review the critiques raised for previous MTEP submissions and explore if there were common problems across submissions. We reviewed a sample of 12 economic submissions to MTEP representing 50 % of 24 sets of guidance issued to July 2015. For each submission, we reviewed the External Assessment Centre's (EAC) report and the guidance document produced by NICE. We identified the main problems raised by the EAC's assessments and the committee's considerations for each submission, and explored strategies for improvement. We found that the identification and measurement of costs and consequences are the main shortcomings within economic submissions to MTEP. Together, these shortcomings accounted for 42 % of criticisms by the EACs among the reviewed submissions. In certain circumstances problems with these shortcomings may be unavoidable, for example, if there is a limited evidence base for the device being appraised. Nevertheless, strategies can often be adopted to improve submissions, including the use of more appropriate time horizons, whilst cost and resource use information should be taken, where possible, from nationally representative sources.

The HubBLe Trial: haemorrhoidal artery ligation (HAL) versus rubber band ligation (RBL) for symptomatic second- and third-degree haemorrhoids: a multicentre randomised controlled trial and health-economic evaluation.

BACKGROUND: Optimal surgical intervention for low-grade haemorrhoids is unknown. Rubber band ligation (RBL) is probably the most common intervention. Haemorrhoidal artery ligation (HAL) is a novel alternative that may be more efficacious. OBJECTIVE: The comparison of HAL with RBL for the treatment of grade II/III haemorrhoids. DESIGN: A multicentre, parallel-group randomised controlled trial. PERSPECTIVE: UK NHS and Personal Social Services. SETTING: 17 NHS Trusts. PARTICIPANTS: Patients aged ≥ 18 years presenting with grade II/III (second- and third-degree) haemorrhoids, including those who have undergone previous RBL. INTERVENTIONS: HAL with Doppler probe compared with RBL. OUTCOMES: Primary outcome - recurrence at 1 year post procedure; secondary outcomes - recurrence at 6 weeks; haemorrhoid severity score; European Quality of Life-5 Dimensions, 5-level version (EQ-5D-5L); Vaizey incontinence score; pain assessment; complications; and cost-effectiveness. RESULTS: A total of 370 participants entered the trial. At 1 year post procedure, 30% of the HAL group had evidence of recurrence compared with 49% after RBL [adjusted odds ratio (OR) = 2.23, 95% confidence interval (CI) 1.42 to 3.51; p = 0.0005]. The main reason for the difference was the number of extra procedures required to achieve improvement/cure. If a single HAL is compared with multiple RBLs then only 37.5% recurred in the RBL arm (adjusted OR 1.35, 95% CI 0.85 to 2.15; p = 0.20). Persistence of significant symptoms at 6 weeks was lower in both arms than at 1 year (9% HAL and 29% RBL), suggesting significant deterioration in both groups over the year. Symptom score, EQ-5D-5L and Vaizey score improved in both groups compared with baseline, but there was no difference between interventions. Pain was less severe and of shorter duration in the RBL group; most of the HAL group who had pain had mild to moderate pain, resolving by 3 weeks. Complications were low frequency and not significantly different between groups. It appeared that HAL was not cost-effective compared with RBL. In the base-case analysis, the difference in mean total costs was £1027 higher for HAL. Quality-adjusted life-years (QALYs) were higher for HAL; however, the difference was very small (0.01) resulting in an incremental cost-effectiveness ratio of £104,427 per additional QALY. CONCLUSIONS: At 1 year, although HAL resulted in fewer recurrences, recurrence was similar to repeat RBL. Symptom scores, complications, EQ-5D-5L and continence score were no different, and patients had more pain in the early postoperative period after HAL. HAL is more expensive and unlikely to be cost-effective in terms of incremental cost per QALY. LIMITATIONS: Blinding of participants and site staff was not possible. FUTURE WORK: The incidence of recurrence may continue to increase with time. Further follow-up would add to the evidence regarding long-term clinical effectiveness and cost-effectiveness. The polysymptomatic nature of haemorrhoidal disease requires a validated scoring system, and the data from this trial will allow further assessment of validity of such a system. These data add to the literature regarding treatment of grade II/III haemorrhoids. The results dovetail with results from the eTHoS study [Watson AJM, Hudson J, Wood J, Kilonzo M, Brown SR, McDonald A, et al. Comparison of stapled haemorrhoidopexy with traditional excisional surgery for haemorrhoidal disease (eTHoS): a pragmatic, multicentre, randomised controlled trial. Lancet 2016, in press.] comparing stapled haemorrhoidectomy with excisional haemorrhoidectomy. Combined results will allow expansion of analysis, allowing surgeons to tailor their treatment options to individual patients. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41394716. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 88. See the NIHR Journals Library website for further project information.