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.

Clinical Effectiveness of Intravitreal Therapy With Ranibizumab vs Aflibercept vs Bevacizumab for Macular Edema Secondary to Central Retinal Vein Occlusion: A Randomized Clinical Trial.

IMPORTANCE: The comparative clinical effectiveness of ranibizumab, aflibercept, and bevacizumab for the management of macular edema due to central retinal vein occlusion (CRVO) is unclear. OBJECTIVE: To determine whether intravitreal aflibercept or bevacizumab compared with ranibizumab results in a noninferior mean change in vision at 100 weeks for eyes with CRVO-related macular edema. DESIGN, SETTING, AND PARTICIPANTS: This prospective, 3-arm, double-masked, randomized noninferiority trial (Lucentis, Eylea, Avastin in Vein Occlusion [LEAVO] Study) took place from December 12, 2014, through December 16, 2016, at 44 UK National Health Service ophthalmology departments. Inclusion criteria included age 18 years or older, visual impairment due to CRVO-related macular edema of less than 12 months with best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter score (approximate Snellen equivalent) in the study eye between 19 (20/400) and 78 (20/32), and spectral domain optical coherence tomography imaging central subfield thickness of 320 µm or greater. Data were analyzed from March 4, 2019, to April 26, 2019. INTERVENTIONS: Participants were randomized (1:1:1) to receive repeated intravitreal injections of ranibizumab (0.5 mg/0.05 mL) (n = 155), aflibercept (2.0 mg/0.05 mL) (n = 154), or bevacizumab (1.25 mg/0.05 mL) (n = 154) for 100 weeks. MAIN OUTCOMES AND MEASURES: Adjusted mean change in BCVA in the study eye at 100 weeks wherein noninferiority was concluded if the lower bounds of the 95% CI of both the intention-to-treat and the per protocol analyses were above -5 letters. RESULTS: Of 463 participants, 265 (57.2%) were male, with a mean (SD) age of 69.1 (13.0) years. The mean (SD) gain in BCVA letter score was 12.5 (21.1) for ranibizumab, 15.1 (18.7) for aflibercept, and 9.8 (21.4) for bevacizumab at 100 weeks. Aflibercept was noninferior to ranibizumab (intention-to-treat-adjusted mean BCVA difference, 2.23 letters; 95% CI, -2.17 to 6.63 letters; P < .001). Bevacizumab was not noninferior to ranibizumab (intention-to-treat-adjusted mean BCVA difference, -1.73 letters; 95% CI, -6.12 to 2.67 letters; P = .07). The per protocol analysis conclusions were similar. Fewer mean injections were given in the aflibercept group (10.0) than in the ranibizumab (11.8) group (mean difference at 100 weeks, -1.9; 95% CI, -2.9 to -0.8). CONCLUSIONS AND RELEVANCE: Mean changes in vision after treatment of macular edema due to CRVO were no worse using aflibercept compared with ranibizumab. Mean changes in vision using bevacizumab compared with ranibizumab were inconclusive regarding vision outcomes (ie, the change in visual acuity from baseline, on average, may be worse or may not be worse when using bevacizumab compared with ranibizumab). TRIAL REGISTRATION: ISRCTN13623634.

Ensuring trial conduct is consistent with trial design: assumption is the enemy of quality.

'Assumptions are made and most assumptions are wrong' (Albert Einstein) Clinical trial conduct must be consistent with trial design, yet conducting the trial according to plan remains a major challenge.We discuss the importance of optimal co-applicant team formation in trial leadership, appropriate delegation of tasks and staff supervision arrangements. Finally, we discuss five standard documents which we believe require particular attention. With appropriate engagement by or with co-applicants during the preparation of these five standard documents, we believe many of the pitfalls trials commonly experience can be avoided. The risks inherent in failing to identify and address mistaken assumptions during the preparation of these documents are discussed and recommendations for best practice suggested.

Dementia and Imagination: a mixed-methods protocol for arts and science research.

INTRODUCTION: Dementia and Imagination is a multidisciplinary research collaboration bringing together arts and science to address current evidence limitations around the benefits of visual art activities in dementia care. The research questions ask: Can art improve quality of life and well-being? If it does make a difference, how does it do this-and why? Does it have wider social and community benefits? METHODS AND ANALYSIS: This mixed-methods study recruits participants from residential care homes, National Health Service (NHS) wards and communities in England and Wales. A visual art intervention is developed and delivered as 1×2-hour weekly group session for 3 months in care and community settings to N=100 people living with dementia. Quantitative and qualitative data are collected at 3 time points to examine the impact on their quality of life, and the perceptions of those who care for them (N=100 family and professional carers). Repeated-measures systematic observations of well-being are obtained during the intervention (intervention vs control condition). The health economics component conducts a social return on investment evaluation of the intervention. Qualitative data are collected at 3 time points (n=35 carers/staff and n=35 people living with dementia) to explore changes in social connectedness. Self-reported outcomes of the intervention delivery are obtained (n=100). Focus groups with intervention participants (n=40) explore perceptions of impact. Social network analysis of quantitative and qualitative data from arts and healthcare professionals (N=100) examines changes in perceptions and practice. ETHICS AND DISSEMINATION: The study is approved by North Wales Research Ethics Committee-West. A range of activities will share the research findings, including international and national academic conferences, quarterly newsletters and the project website. Public engagement projects will target a broad range of stakeholders. Policy and practice summaries will be developed. The visual art intervention protocol will be developed as a freely available practitioners guide.

REMCARE: Pragmatic Multi-Centre Randomised Trial of Reminiscence Groups for People with Dementia and their Family Carers: Effectiveness and Economic Analysis.

BACKGROUND: Joint reminiscence groups, involving people with dementia and family carers together, are popular, but the evidence-base is limited. This study aimed to assess the effectiveness and cost-effectiveness of joint reminiscence groups as compared to usual care. METHODS: This multi-centre, pragmatic randomised controlled trial had two parallel arms: intervention group and usual-care control group. A restricted dynamic method of randomisation was used, with an overall allocation ratio of 1:1, restricted to ensure viable sized intervention groups. Assessments, blind to treatment allocation, were carried out at baseline, three months and ten months (primary end-point), usually in the person's home. Participants were recruited in eight centres, mainly through NHS Memory Clinics and NHS community mental health teams. Included participants were community resident people with mild to moderate dementia (DSM-IV), who had a relative or other care-giver in regular contact, to act as informant and willing and able to participate in intervention. 71% carers were spouses. 488 people with dementia (mean age 77.5)were randomised: 268 intervention, 220 control; 350 dyads completed the study (206 intervention, 144 control). The intervention evaluated was joint reminiscence groups (with up to 12 dyads) weekly for twelve weeks; monthly maintenance sessions for further seven months. Sessions followed a published treatment manual and were held in a variety of community settings. Two trained facilitators in each centre were supported by volunteers. Primary outcome measures were self-reported quality of life for the person with dementia (QoL-AD), psychological distress for the carer (General Health Questionnaire, GHQ-28). Secondary outcome measures included: autobiographical memory and activities of daily living for the person with dementia; carer stress for the carer; mood, relationship quality and service use and costs for both. RESULTS: The intention to treat analysis (ANCOVA) identified no differences in outcome between the intervention and control conditions on primary or secondary outcomes (self-reported QoL-AD mean difference 0.07 (-1.21 to 1.35), F = 0.48, p = 0.53). Carers of people with dementia allocated to the reminiscence intervention reported a significant increase in anxiety on a General Health Questionnaire-28 sub-scale at the ten month end-point (mean difference 1.25 (0.25 to 2.26), F = 8.28, p = 0.04). Compliance analyses suggested improved autobiographical memory, quality of life and relationship quality for people with dementia attending more reminiscence sessions, however carers attending more groups showed increased care-giving stress. Economic analyses from a public sector perspective indicated that joint reminiscence groups are unlikely to be cost-effective. There were no significant adverse effects attributed to the intervention. Potential limitations of the study include less than optimal attendance at the group sessions--only 57% of participants attended at least half of the intervention sessions over the 10 month period, and a higher rate of study withdrawal in the control group. CONCLUSIONS: This trial does not support the clinical effectiveness or cost-effectiveness of joint reminiscence groups. Possible beneficial effects for people with dementia who attend sessions as planned are offset by raised anxiety and stress in their carers. The reasons for these discrepant outcomes need to be explored further, and may necessitate reappraisal of the movement towards joint interventions. TRIAL REGISTRATION: ISRCTN Registry ISRCTN42430123.

The use of the EQ-5D as a measure of health-related quality of life in people with dementia and their carers.

PURPOSE: To assess the acceptability, validity and inter-rater agreement of self- and family carer proxy ratings of the EQ-5D as a generic health-related quality of life (HRQOL) measure, in people with mild to moderate dementia (PwD) living in the community. A secondary aim was to identify the most important factors influencing self- and family carer proxy ratings of HRQOL, distinguishing between spouse and adult child caregiver ratings. METHODS: Cross-sectional study of 488 dyads using the EQ-5D. Inter-rater agreement was examined using weighted kappa scores, and validity by investigating the association of self- and family carer ratings with clinical variables. Factors affecting HRQOL ratings were analysed using multivariate regression. RESULTS: The response rate of the EQ-5D was satisfactory; however, agreement between self- and family carer ratings was poor. The most important predictors of PwD and carer ratings of the PwD's HRQOL were family carer ratings of activities of daily living and mood. Anxiety experienced by the PwD was a significant predictor of self-rated HRQOL, whereas depressive symptoms independently predicted family carer ratings. The type of the caregiving relationship influenced carer ratings of HRQOL, whereby sons and daughters rated HRQOL lower for the PwD compared with spousal caregivers. CONCLUSIONS: People with mild to moderate dementia are able to rate their own HRQOL through a brief generic instrument; however, self-ratings consistently differ from family carer ratings, which should be acknowledged in cost-effectiveness analyses. Spouse caregivers rate HRQOL for the PwD more positively compared to adult children.

Self- and Carer-Rated Pain in People With Dementia: Influences of Pain in Carers.

CONTEXT: Although pain is frequent in people with dementia (PwD), evidence on the prevalence and factors influencing ratings of pain in dementia is limited. Carer variables are often associated with bias in proxy ratings of pain, but few studies have examined the role of caregiver pain in influencing these ratings. OBJECTIVES: This study explored the prevalence of pain in PwD in a large U.K. SAMPLE: A secondary aim was to identify factors influencing ratings of pain in people with mild to moderate dementia and whether carer pain systematically influences proxy ratings. METHODS: This was a cross-sectional study of 488 caregiving dyads living in the community. Self- and carer-rated pain was assessed as part of the EuroQoL-5D (EQ-5D). Depression and anxiety for the PwD were measured by the Cornell Scale for Depression in Dementia and the Rating of Anxiety in Dementia Scale. The Hospital Anxiety and Depression Scale was used to measure anxiety and depressive symptoms in carers. Using logistic regression modeling, we examined the relationship between self- and carer-rated (proxy) pain in PwD and psychological distress, functional ability, and health status. Carer variables included self-rated health, strain, anxiety, depression, and caregiver pain. RESULTS: A total of 45% of PwD reported pain, whereas carer-rated pain was higher (59%). Self-rated pain was more frequent in those with lower self-rated health (adjusted odds ratio [AOR] 0.97; 95% CI 0.96-0.99, P ≤ 0.001) and higher anxiety (AOR 1.07; 95% CI 1.01-1.12, P = 0.013). Carer-rated (proxy) pain was additionally predicted by poor proxy-rated health in the PwD (AOR 0.98; 95% CI 0.96-0.99, P = 0.006) and carers' own experience of pain (AOR 0.36; 95% CI 0.21-0.63, P ≤ 0.001). CONCLUSION: Our results indicate that pain is very frequently reported in PwD and that the presence of pain is associated with high levels of anxiety. Caregiver pain affects carers' perceptions of pain in PwD.

Self and carer perspectives of quality of life in dementia using the QoL-AD.

OBJECTIVE: Quality of life (QoL) is one of the most important outcomes in improving well-being in people with dementia (PwD). The primary aim of the present study was to compare self and carer ratings of QoL in PwD and to identify the most important factors influencing self and carer ratings. METHODS: We conducted a cross-sectional analytic study of 488 dyads using the Quality of Life in Alzheimer's Disease scale, demographics, data on self-rated health, and clinical characteristics. RESULTS: Higher levels of self-rated health in PwD were associated with higher self-rated QoL after controlling for depression and activities of daily living. When the carer experienced less stress related to caregiving, the PwD reported better QoL. Higher carer-rated QoL was associated with less carer stress, better health for the family carer, and the PwD being of younger age. When carers lived with the PwD, and reported lower levels of depression and better functional ability for their relative, carer-rated QoL was higher. CONCLUSIONS: The self-rated health of PwD and carers influences the ratings they make of the QoL of the PwD indicating that it is an important influence on QoL in this population.

Qualitative exploration of the suitability of capability based instruments to measure quality of life in family carers of people with dementia.

Background. In an ageing population, many individuals find themselves becoming a carer for an elderly relative. This qualitative study explores aspects of quality of life affected by caring for a person with dementia, with the aim of identifying whether capability based questionnaires are suitable for measuring carer quality of life. Methods. Semistructured interviews lasting up to an hour were conducted, November 2010-July 2011, with eight family carers of people with dementia. Interviews typically took place at the participants' homes and were recorded and transcribed verbatim. Framework analysis was used to code and analyse data. Domains from three capability based questionnaires (ICECAP-O, Carer Experience Scale, and ASCOT) were used as initial codes. Similar codes were grouped into categories, and broader themes were developed from these categories. Results. Four themes were identified: social network and relationships; interactions with agencies; recognition of role; and time for oneself. Conclusions. By identifying what affects carers' quality of life, an appropriate choice can be made when selecting instruments for future carer research. The themes identified had a high degree of overlap with the capability instruments, suggesting that the capabilities approach would be suitable for future research involving carers of people with dementia.

Health economics research into supporting carers of people with dementia: a systematic review of outcome measures.

Advisory bodies, such as the National Institute for Health and Clinical Excellence (NICE) in the UK, advocate using preference based instruments to measure the quality of life (QoL) component of the quality-adjusted life year (QALY). Cost per QALY is used to determine cost-effectiveness, and hence funding, of interventions. QALYs allow policy makers to compare the effects of different interventions across different patient groups. Generic measures may not be sensitive enough to fully capture the QoL effects for certain populations, such as carers, so there is a need to consider additional outcome measures, which are preference based where possible to enable cost-effectiveness analysis to be undertaken. This paper reviews outcome measures commonly used in health services research and health economics research involving carers of people with dementia. An electronic database search was conducted in PubMed, Medline, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, the National Health Service Economic Evaluation Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment database. Studies were eligible for inclusion if they included an outcome measure for carers of people with dementia. 2262 articles were identified. 455 articles describing 361 studies remained after exclusion criteria were applied. 228 outcome measures were extracted from the studies. Measures were categorised into 44 burden measures, 43 mastery measures, 61 mood measures, 32 QoL measures, 27 social support and relationships measures and 21 staff competency and morale measures. The choice of instrument has implications on funding decisions; therefore, researchers need to choose appropriate instruments for the population being measured and the type of intervention undertaken. If an instrument is not sensitive enough to detect changes in certain populations, the effect of an intervention may be underestimated, and hence interventions which may appear to be beneficial to participants are not deemed cost-effective and are not funded. If this is the case, it is essential that additional outcome measures which detect changes in broader QoL are included, whilst still retaining preference based utility measures such as EQ-5D to allow QALY calculation for comparability with other interventions.

The AgeWell study of behavior change to promote health and wellbeing in later life: study protocol for a randomized controlled trial.

BACKGROUND: Lifestyle factors playing a role in the development of late-life disability may be modifiable. There is a need for robust evidence about the potential for prevention of disability through behavior change interventions. METHODS/DESIGN: This feasibility study involves the development, implementation and initial testing of a behavior change intervention in a naturalistic setting. A small-scale randomized controlled trial (RCT) will investigate the implementation of a goal-setting intervention aimed at promoting behavior change in the domains of physical and cognitive activity in the context of a community resource center for over-50s. Healthy older participants attending the center (n = 75) will be randomized to one of three conditions: control (an interview involving a general discussion about the center); goal-setting (an interview involving identification of up to five personal goals in the domains of physical activity, cognitive activity, diet and health, and social engagement); or goal-setting with mentoring (the goal-setting interview followed by bi-monthly telephone mentoring). All participants will be reassessed after 12 months. Primary outcomes are levels of physical and cognitive activity. Secondary outcomes address psychosocial (self-efficacy, mood, quality of life), cognitive (memory and executive function), and physical fitness (functional and metabolic) domains. Cost-effectiveness will also be examined. DISCUSSION: This study will provide information about the feasibility of a community-based lifestyle intervention model for over-50s and of the implementation of a goal-setting intervention for behavior change, together with initial evidence about the short-term effects of goal-setting on behavior. TRIAL REGISTRATION: Current Controlled Trials ISRCTN30080637 (http://www.controlled-trials.com).

Psychological morbidity of farmers and non-farming population: results from a UK survey.

The relatively high rate of suicide among UK farmers suggests that they may suffer greater mental health problems than the general population. This paper provides a comparison of the psychological morbidity of farmers and their partners/spouses with non-farmers. The General Health Questionnaire (GHQ-12) was administered using face-to-face interviews with 784 attendees of agricultural shows in the UK. Results show that GHQ-12 scores for farmers and their partners/spouses were significantly higher (P < 0.001) than those for the non-farming population, indicating higher psychological morbidity among farmer families. Approximately 35% of farmers had scores 12 and higher (recommended cut-off for psychiatric disorders), compared to 27% of non-farmers. Within the farmers group, male respondents, those aged from 45 to 64, self-employed or not in paid employment, having a non-supervisory position and living in a rural area were characterized by higher mean GHQ-12 scores compared to correspondent subgroups from the non-farming population.

A systematic review of the cost-effectiveness of interventions for supporting informal caregivers of people with dementia residing in the community.

BACKGROUND: Dementia places a huge demand on healthcare services; however, a large proportion of the cost is borne by informal caregivers. With the number of people affected by dementia set to increase in the future, there is a need for research to consider the effects of interventions on informal caregivers as well as on the individuals with dementia. This paper seeks to systematically review the existing evidence on the cost-effectiveness of interventions to support informal caregivers of people with dementia residing in the community. METHODS: A range of electronic databases was searched. Studies were included if both costs and outcome measures for informal caregivers of people with dementia residing in the community were reported for an intervention. Both pharmacological and non-pharmacological interventions were included. Quality of study was assessed using the Drummond ten-item checklist for economic evaluations and results were presented through narrative synthesis. RESULTS: Twelve studies were included in the review; of these only four reported a significant difference in the outcome measure for caregivers. CONCLUSIONS: At present few published studies report costs in enough detail to provide evidence of the effectiveness and cost-effectiveness of interventions for supporting caregivers. Future trials need to collect caregiver data alongside patient data in order to increase the evidence base for intervention effectiveness. Further research is required to establish the effectiveness and cost-effectiveness of both pharmacological and non-pharmacological approaches.

Reminiscence groups for people with dementia and their family carers: pragmatic eight-centre randomised trial of joint reminiscence and maintenance versus usual treatment: a protocol.

BACKGROUND: The growing number of people with dementia, and the increasing cost of care, provides a major incentive to develop and test methods of supporting them in the community for longer. Most attention has been given to pharmacological interventions, but there is increasing recognition that psychosocial interventions may be equally effective, even preferable where medication has negative side-effects. Reminiscence groups, run by professionals and volunteers, which use photographs, recordings and other objects to trigger personal memories are probably the most popular therapeutic approach to working with people with dementia, but there is little evidence for their effectiveness and cost-effectiveness. The recent inclusion of family carers in groups with people with dementia, notably in our own pilot studies, has generated informal evidence that this joint approach improves relationships between people with dementia and their carers, and benefits both. DESIGN AND METHODS: This multi-centre, pragmatic randomised controlled trial (RCT) to assess the effectiveness and cost-effectiveness of joint reminiscence groups for people with dementia and their family care-givers has two parallel arms--an intervention group and a control group who receive care as usual. The intervention consists of joint reminiscence groups held weekly for twelve consecutive weeks, followed by monthly maintenance sessions for a further seven months.The primary outcome measures are the quality of life of people with dementia, as assessed by QoL-AD, and their care-givers' mental health as assessed by the GHQ-28. Secondary outcomes include: the autobiographical memories of people with dementia; the quality of the relationship between them and their care-givers; and the levels of depression and anxiety felt by them and their care-giver. Using a 5% significance level, comparison of 200 pairs attending joint reminiscence groups with 200 pairs receiving usual treatment will yield 80% power to detect a standardised difference of 0.38 in the QoL-AD rated by the person with dementia and 0.28 in the GHQ-28 or carer-rated QoL-AD. The trial will include a cost-effectiveness analysis from a public sector perspective. DISCUSSION: Our Cochrane review (2005) on reminiscence therapy for people with dementia did not identify any rigorous trials or economic analyses in this field. TRIAL REGISTRATION: ISRCTN42430123.

Economic evaluation alongside pragmatic randomised trials: developing a standard operating procedure for clinical trials units.

BACKGROUND: There is wide recognition that pragmatic randomised trials are the best vehicle for economic evaluation. This is because trials provide the best chance of ensuring internal validity, not least through the rigorous prospective collection of patient-specific data. Furthermore the marginal cost of collecting economic data alongside clinical data is typically modest. UK Clinical Research Collaboration (UKCRC) does not require a standard operating procedure (SOP) for economic evaluation as a prerequisite for trial unit registration. We judge that such a SOP facilitates the integration of health economics into trials. METHODS: A collaboration between health economists and trialists at Bangor University led to the development of a SOP for economic evaluation alongside pragmatic trials, in addition to the twenty SOPs required by UKCRC for registration, which include randomisation, data management and statistical analysis. RESULTS: Our recent telephone survey suggests that no other UKCRC-registered trials unit currently has an economic SOP. CONCLUSION: We argue that UKCRC should require, from all Trials Units undertaking economic evaluation and seeking registration or re-registration, a SOP for economic evaluation as one of their portfolio of supporting SOPs.

Comparative assessment of migrant farm worker health in conventional and organic horticultural systems in the United Kingdom.

This study describes the self-reported health and well-being status of field and packhouse workers in UK vegetable horticulture, and tests the null hypothesis that there is no difference in the self-reported health of workers on organic and conventional horticultural farms. The majority of those sampled were migrant workers (93%) from Bulgaria, Latvia, Lithuania, Poland, Russia and the Ukraine. More than 95% of the respondents were aged 18-34 and recruited through university agricultural faculties in East European or employed via UK agencies. The health of 605 farm workers (395 males and 210 females) was measured through the use of four standard health instruments. Farm workers' health was significantly poorer than published national norms for three different health instruments (Short Form 36, EuroQol EQ-5D and the Visual Analogue Scale). There were no significant differences in the health status of farm workers between conventional and organic farms for any of these three instruments. However, organic farm workers scored higher on a fourth health instrument the Short Depression Happiness Scale (SDHS) indicating that workers on organic farms were happier than their counterparts working on conventional farms. Multiple regression analysis suggested that the difference in the SDHS score for organic and conventional farms is closely related to the range and number of tasks the workers performed each day. These findings suggest that a great deal of improvement in the self-reported health of farmers will need to occur before organic farms meet the requirements of the 'Principle of Health' as described by IFOAM. Ensuring that farm workers have a varied range of tasks could be a cost effective means of improving self-reported health status in both organic and conventional farming systems.

Cost-utility analysis of osteopathy in primary care: results from a pragmatic randomized controlled trial.

BACKGROUND: Spinal pain is common and costly to health services and society. Management guidelines have encouraged primary care referral for spinal manipulation, but the evidence base is weak. More economic evaluations alongside pragmatic trials have been recommended. OBJECTIVE: Our aim was to assess the cost-utility of a practice-based osteopathy clinic for subacute spinal pain. METHODS: A cost-utility analysis was performed alongside a pragmatic single-centre randomized controlled trial in a primary care osteopathy clinic accepting referrals from 14 neighbouring practices in North West Wales. Patients with back pain of 2-12 weeks duration were randomly allocated to treatment with osteopathy plus usual GP care or usual GP care alone. Costs were measured from a National Health Service (NHS) perspective. All primary and secondary health care interventions recorded in GP notes were collected for the study period. We calculated quality adjusted life year (QALY) gains based on EQ-5D responses from patients in the trial, and then cost per QALY ratios. Confidence intervals (CIs) were estimated using non-parametric bootstrapping. RESULTS: Osteopathy plus usual GP care was more effective but resulted in more health care costs than usual GP care alone. The point estimate of the incremental cost per QALY ratio was 3560 pounds (80% CI 542 pounds-77,100 pounds). Sensitivity analysis examining spine-related costs alone and total costs excluding outliers resulted in lower cost per QALY ratios. CONCLUSION: A primary care osteopathy clinic may be a cost-effective addition to usual GP care, but this conclusion was subject to considerable random error. Rigorous multi-centre studies are needed to assess the generalizability of this approach.

Economic evaluation of treatments for children with severe behavioural problems.

BACKGROUND: Disruptive behaviour disorders, including conduct disorder, affect at least 10% of children and are the most common reasons for referral to children's mental health services. The long-term economic impact on society of unresolved conduct disorder can exceed pound sterling 1 million for one individual over their lifetime. AIMS OF THE STUDY: The aim of this study was to estimate, from a multi-sectoral service perspective, the longer term cost-effectiveness of an intensive practice based parenting programme for children with severe behavioural problems as compared to a standard treatment, on a pilot basis. METHODS: A six-month pragmatic controlled trial was conducted involving forty-two families who had been referred to a Child and Adolescent Mental Health Service (CAMHS) because of severe child behavioural problems. The families were randomly allocated into either the standard or intensive, practice-based treatment arms of the trial. At baseline, children were aged 2 to 10 years. The externalising T-scale of the Child Behaviour Check List (CBCL) was used as the primary outcome measure. Follow-up studies were conducted at 6 months and four years post-intervention. At the four-year follow up point the two treatments were subjected to an incremental cost-effectiveness analysis. This analysis was enabled by the collection of cost data with respect to the provision of the intensive and standard treatments in terms of therapeutic contact time and also participants' use of health, special educational and social services usage by means of a Client Service Receipt Inventory. RESULTS: Both groups exhibited improved behaviour at six month follow-up, but only the practice based treatment group showed sustained improvement at the four-year follow-up. An independent t-test revealed a significant difference between group mean scores at four-year follow-up (p = 0.027). The research found a median bootstrap ICER estimate of pound sterling 224 From the cost-effectiveness acceptability curve (CEAC) it was found that 89.6% of the cost-effectiveness plane represented a cost saving over the control intervention while 99.9% represented an improvement in effect. Therefore the intensive intervention could not be said to differ significantly from the control intervention on the basis of costs or effects. However under certain circumstances requiring judgement the intensive intervention could be cost-effective. DISCUSSION: Training interventions for the parents of children with severe conduct disorders currently take the form of a number of behavioural strategies provided by a CAMHS team including the reinforcement of appropriate behaviours and parent record-keeping. An alternative treatment was then considered that included all the aspects provided by the standard treatment (with the exception of agreeing written goals) and also added five-hour sessions of unit-based treatment during which videotaped recording of parent-child interactions were used to give feedback to parents and to provide the opportunity for behavioural rehearsal. The findings of the current research indicate that this alternative treatment may be more cost-effective than the standard intervention under certain circumstances. CONCLUSIONS: It can be concluded on a pilot basis that while the CEAC failed to show a significant difference between costs and effects for the intensive treatment, under circumstances of resource/effect trade offs the treatment could be said to be cost-effective. IMPLICATIONS FOR HEALTH CARE PROVISION, USE AND POLICIES: Health and social care policy and commissioning must be evidence based. Although the analysis in this paper should be considered a pilot due to the small sample size our results suggest that investment by health services and social services in practice-based parenting interventions may well be less costly and more effective in the longer-run than the standard practice involving giving management advice to parents. IMPLICATIONS FOR FURTHER RESEARCH: It would be of interest for further research to continue to follow up the work done in this study with a larger cohort of subjects to further establish the effective components of parenting programmes and their relative costs and benefits both at intervention and over time.