Emma Simpson

Involving users in the delivery and evaluation of mental health services: systematic review

Abstract Objectives: To identify evidence from comparative studies on the effects of involving users in the delivery and evaluation of mental health services. Data sources: English language articles published between January 1966 and October 2001 found by searching electronic databases. Study selection: Systematic review of randomised controlled trials and other comparative studies of involving users in the delivery or evaluation of mental health services. Data extraction:Patterns of delivery of services by employees who use or who used to use the service and professional employees and the effects on trainees, research, or clients of mental health services. Results: Five randomised controlled trials and seven other comparative studies were identified. Half of the studies considered involving users in managing cases. Involving users as employees of mental health services led to clients having greater satisfaction with personal circumstances and less hospitalisation. Providers of services who had been trained by users had more positive attitudes toward users. Clients reported being less satisfied with services when interviewed by users. Conclusions: Users can be involved as employees, trainers, or researchers without detrimental effect. Involving users with severe mental disorders in the delivery and evaluation of services is feasible.

Systematic review of the efficacy of cilostazol, naftidrofuryl oxalate and pentoxifylline for the treatment of intermittent claudication

A systematic review and network meta‐analysis was undertaken to consider the evidence for the efficacy and tolerability of placebo, cilostazol, naftidrofuryl oxalate and pentoxifylline in patients with intermittent claudication due to peripheral arterial disease (PAD).

Intensity-modulated radiotherapy for the treatment of prostate cancer: a systematic review and economic evaluation

BACKGROUND Prostate cancer (PC) is the most common cancer in men in the UK. Radiotherapy (RT) is a recognised treatment for PC and high-dose conformal radiotherapy (CRT) is the recommended standard of care for localised or locally advanced tumours. Intensity-modulated radiotherapy (IMRT) allows better dose distributions in RT. OBJECTIVE This report evaluates the clinical effectiveness and cost-effectiveness of IMRT for the radical treatment of PC. DATA SOURCES The following databases were searched: MEDLINE (1950-present), EMBASE (1980-present), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982-present), BIOSIS (1985-present), the Cochrane Database of Systematic Reviews (1991-present), the Cochrane Controlled Trials Register (1991-present), the Science Citation Index (1900-present) and the NHS Centre for Reviews and Dissemination databases (Database of Abstracts of Reviews of Effects, NHS Economic Evaluation Database, Health Technology Assessment) (1991-present). MEDLINE In-Process & Other Non-Indexed Citations was searched to identify any studies not yet indexed on MEDLINE. Current research was identified through searching the UK Clinical Research Network, National Research Register archive, the Current Controlled Trials register and the Medical Research Council Clinical Trials Register. In addition, abstracts of the American Society of Clinical Oncology, the American Society for Therapeutic Radiology and Oncology, and European Society for Therapeutic Radiology and Oncology conferences were browsed. REVIEW METHODS A systematic literature review of the clinical effectiveness and cost-effectiveness of IMRT in PC was conducted. Comparators were three-dimensional conformal radiotherapy (3DCRT) or radical prostatectomy. Outcomes sought were overall survival, biochemical [prostate-specific antigen (PSA)] relapse-free survival, toxicity and health-related quality of life (HRQoL). Fifteen electronic bibliographic databases were searched in January 2009 and updated in May 2009, and the reference lists of relevant articles were checked. Studies only published in languages other than English were excluded. An economic model was developed to examine the cost-effectiveness of IMRT in comparison to 3DCRT. Four scenarios were modelled based on the studies which reported both PSA survival and late gastrointestinal (GI) toxicity. In two scenarios equal PSA survival was assumed for IMRT and 3DCRT, the other two having greater PSA survival for the IMRT cohort. As there was very limited data on clinical outcomes, the model estimates progression to clinical failure and PC death from the surrogate outcome of PSA failure. RESULTS No randomised controlled trials (RCTs) of IMRT versus 3DCRT in PC were available, but 13 non-randomised studies comparing IMRT with 3DCRT were found, of which five were available only as abstracts. One abstract reported overall survival. Biochemical relapse-free survival was not affected by treatment group, except where there was a dose difference between groups, in which case higher dose IMRT was favoured over lower dose 3DCRT. Most studies reported an advantage for IMRT in GI toxicity, attributed to increased conformality of treatment compared with 3DCRT, particularly with regard to volume of rectum treated. There was some indication that genitourinary toxicity was worse for patients treated with dose escalated IMRT, although most studies did not find a significant treatment effect. HRQoL improved for both treatment groups following radiotherapy, with any group difference resolved by 6 months after treatment. No comparative studies of IMRT versus prostatectomy were identified. No comparative studies of IMRT in PC patients with bone metastasis were identified. LIMITATIONS The strength of the conclusions of this review are limited by the lack of RCTs, and any comparative studies for some patient groups. CONCLUSIONS The comparative data of IMRT versus 3DCRT seem to support the theory that higher doses, up to 81 Gy, can improve biochemical survival for patients with localised PC, concurring with data on CRT. The data also suggest that toxicity can be reduced by increasing conformality of treatment, particularly with regard to GI toxicity, which can be more easily achieved with IMRT than 3DCRT. Whether differences in GI toxicity between IMRT and 3DCRT are sufficient for IMRT to be cost-effective is uncertain, depending on the difference in incidence of GI toxicity, its duration and the cost difference between IMRT and 3DCRT.

A Systematic Review and Economic Evaluation of Cilostazol, Naftidrofuryl Oxalate, Pentoxifylline and Inositol Nicotinate for the Treatment of Intermittent Claudication in People with Peripheral Arterial Disease

BACKGROUND Peripheral arterial disease (PAD) is a condition in which there is blockage or narrowing of the arteries that carry blood to the legs and arms. It is estimated to affect around 4.5% of people aged between 55 and 74 years within the UK. The most common symptom of PAD is intermittent claudication (IC), characterised by pain in the legs on walking that is relieved with rest. OBJECTIVE To assess the effectiveness and cost-effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate, compared with no vasoactive drugs, for IC due to PAD in adults whose symptoms continue despite a period of conventional management. DATA SOURCE Electronic bibliographic databases were searched during April to June 2010 (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings Citation Index, BIOSIS Previews). REVIEW METHODS Effectiveness outcomes sought were maximal walking distance (MWD), pain-free walking distance (PFWD), ankle-brachial pressure index, cardiovascular events, mortality, adverse events (AEs) and health-related quality of life (HRQoL). A narrative synthesis was provided for all outcomes and a network meta-analysis was undertaken for the walking distance outcomes. A Markov model was developed to assess the relative cost-effectiveness of the interventions from a NHS perspective over a lifetime. The model has three states: vasoactive drug treatment, no vasoactive drug treatment and death. Each 1-week cycle, patients may continue with the drug, discontinue the drug or die. Regression analysis was undertaken to model the relationship between MWD and utility so that a cost per quality-adjusted life-year (QALY) outcome measure could be presented. Univariate and probabilistic sensitivity analyses were undertaken. All costs and outcomes were discounted at 3.5%. RESULTS Twenty-six randomised controlled trials were identified that met the inclusion criteria for the clinical effectiveness review. There was evidence that walking distance outcomes were significantly improved by both cilostazol and naftidrofuryl oxalate; the 95% credible intervals for the difference from placebo in the logarithm mean change MWD from baseline were 0.108 to 0.337 and 0.181 to 0.762, respectively. It was not possible to include inositol nicotinate within the meta-analysis of MWD and PFWD owing to the lack of 24-month data; however, the shorter-term data did not suggest a significant effect. AEs were minor for all drugs and included headaches and gastrointestinal difficulties. The incidence of serious adverse events (SAEs), including cardiovascular events and mortality, was not increased by the vasoactive drugs compared with placebo; however, most studies had a relatively short follow-up time to address this outcome. HRQoL data were limited. Two studies of limited quality were identified within the review of cost-effectiveness. The de novo model developed suggests that naftidrofuryl oxalate dominates cilostazol and pentoxifylline and has a cost per QALY gained of around £6070 compared with no vasoactive drug. This result is reasonably robust to changes within the key model assumptions. Inositol nicotinate was not included within the main analysis owing to lack of data. However, it is unlikely to be considered to be cost-effective due to its high acquisition cost (£900 vs £100-500 per year for the other drugs). CONCLUSIONS Naftidrofuryl oxalate and cilostazol both appear to be effective treatments for this patient population, with minimal SAEs. However, naftidrofuryl oxalate is the only treatment that is likely to be considered cost-effective. The long-term effectiveness is uncertain and hence a trial comparing cilostazol, naftidrofuryl oxalate and placebo beyond 24 weeks would be beneficial. Outcomes associated with naftidrofuryl oxalate could also be compared with those associated with supervised exercise programmes and angioplasty.

Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation

OBJECTIVES To evaluate the clinical effectiveness and incremental cost-effectiveness of amantadine, oseltamivir and zanamivir for seasonal and post-exposure prophylaxis of influenza. DATA SOURCES A MEDLINE search strategy was used and searches were carried out in July 2007. REVIEW METHODS An independent health economic model was developed based on a review of existing cost-effectiveness models and clinical advice.The model draws together a broad spectrum of evidence relating to the costs and consequences associated with influenza and its prevention. Where direct evidence concerning the effectiveness of prophylaxis within specific model subgroups was lacking, the model uses estimates from mixed subgroups or extrapolates from other mutually exclusive subgroups. RESULTS Twenty-six published references relating to 22 randomised controlled trials (RCTs) were included in the clinical effectiveness review, along with one unpublished report. Eight, six and nine RCTs were included for amantadine, oseltamivir and zanamivir respectively. The study quality was variable and gaps in the evidence base limited the assessment of the clinical effectiveness of the interventions. For seasonal prophylaxis, there was limited evidence for the efficacy of amantadine in preventing symptomatic, laboratory-confirmed influenza (SLCI) in healthy adults [relative risk (RR) 0.40, 95% confidence interval (CI) 0.08-2.03]. Oseltamivir was effective in preventing SLCI, particularly when used in at-risk elderly subjects (RR 0.08, 95% CI 0.01-0.63). The preventative efficacy of zanamivir was most notable in at-risk adults and adolescents (RR 0.17, 95% CI 0.07-0.44), and healthy and at-risk elderly subjects (RR 0.20, 95% CI 0.02-1.72). For post-exposure prophylaxis, data on the use of amantadine were again limited: in adolescents an RR of 0.10 (95% CI 0.03-0.34) was reported for the prevention of SLCI. Oseltamivir was effective in households of mixed composition (RR 0.19, 95% CI 0.08-0.45). The efficacy of zanamivir in post-exposure prophylaxis within households was also reported (RR 0.21, 95% CI 0.13-0.33). Interventions appeared to be well tolerated. Limited evidence was available for the effectiveness of the interventions in preventing complications and hospitalisation and in minimising length of illness and time to return to normal activities. No clinical effectiveness data were identified for health-related quality of life or mortality outcomes. With the exception of at-risk children, the incremental cost-utility of seasonal influenza prophylaxis is expected to be in the range 38,000-428,000 pounds per QALY gained (depending on subgroup). The cost-effectiveness ratios for oseltamivir and zanamivir as post-exposure prophylaxis are expected to be below 30,000 pounds per QALY gained in healthy children, at-risk children, healthy elderly and at-risk elderly individuals. Despite favourable clinical efficacy estimates, the incorporation of recent evidence of viral resistance to amantadine led to it being dominated in every economic comparison. CONCLUSIONS All three interventions showed some efficacy for seasonal and post-exposure prophylaxis. However, weaknesses and gaps in the clinical evidence base are directly relevant to the interpretation of the health economic model and rendered the use of advanced statistical analyses inappropriate. These data limitations should be borne in mind in interpreting the findings of the review.

Cost-effectiveness of disease-modifying therapies in the management of multiple sclerosis for the Medicare population.

OBJECTIVE To evaluate the cost-effectiveness of disease-modifying therapies (DMTs) for the management of multiple sclerosis (MS) compared to best supportive care in the United States. METHODS Cost-effectiveness analysis was undertaken using a state transition model of disease natural history and the impact of DMTs for the representative Medicare beneficiary with MS. Costs and outcomes were evaluated from the health-care payer perspective using a 50-year time horizon. Natural history data were drawn from a longitudinal cohort study. The effectiveness of the DMTs was evaluated through a systematic review. Utility data were taken from a study of patients with clinically definite MS in Nova Scotia. Resource use and cost data were derived from the Sonya Slifka database and associated literature. RESULTS When based on placebo-controlled evidence, the marginal cost-effectiveness of interferon beta (IFNβ) and glatiramer acetate compared to best supportive care is expected to be in excess of

The clinical efficacy of cytotoxic agents in locally advanced or metastatic breast cancer patients pretreated with an anthracycline and a taxane: a systematic review

100,000 per quality-adjusted life-year gained. When evidence from head-to-head trials is incorporated into the model, the cost-effectiveness of 6 MIU IFNβ-1a is expected to be considerably less favorable. Treatment discontinuation upon progression to Expanded Disability Status Scale 7.0 is expected to improve the cost-effectiveness of all DMTs. CONCLUSIONS Further research is required to examine the long-term clinical effectiveness and cost-effectiveness of these therapies. There is no definitive guidance in the United States concerning discontinuation of DMTs; this study suggests that the prudent use of a treatment discontinuation rule may considerably improve the cost-effectiveness of DMTs.

Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with disease-modifying antirheumatic drugs and after the failure of conventional disease-modifying antirheumatic drugs only: systematic review and economic evaluation

INTRODUCTION Currently available evidence does not provide definitive guidance regarding the optimal chemotherapy agents and combinations in anthracycline- and taxane-pretreated advanced breast cancer. We performed a systematic review of controlled clinical trials of the cytotoxic agents currently used for this population in Europe: capecitabine, gemcitabine, vinorelbine, docetaxel, paclitaxel and paclitaxel protein-bound particles. METHOD A systematic review of randomised (RCT) and non-randomised controlled clinical trials (non-RCTs). The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS); secondary outcomes were duration of response (DR), overall response rate (ORR), adverse events and quality of life (QoL). Six electronic databases and grey literature sources were searched; reference tracking was performed on included publications. A narrative synthesis was conducted: heterogeneity of study design and interventions prevented meta-analysis. RESULTS No randomised controlled trial (RCT) found any significant differences between any of the regimens in terms of OS. In terms of PFS, only gemcitabine plus vinorelbine performed significantly better than its comparator, vinorelbine alone. For secondary outcomes, only capecitabine plus bevacizumab had a significantly better outcome than its comparator, capecitabine alone, in terms of ORR. A low quality non-RCT found that both capecitabine monotherapy and a combination of capecitabine plus vinorelbine were significantly more effective than vinorelbine alone in terms of OS and ORR. Across all trials, median OS for these patients typically remained less than 16 months. CONCLUSION The quantity and quality of the available evidence regarding the efficacy of the particular chemotherapy regimens in patients with advanced breast cancer pretreated with an anthracycline and a taxane is extremely limited. New effective therapies are sorely needed in this population.

Thrombophilia testing in people with venous thrombo-embolism: systematic review and cost-effectiveness analysis

OBJECTIVES Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increasing disability, reduced quality of life and substantial costs (as a result of both intervention acquisition and hospitalisation). The objective was to assess the clinical effectiveness and cost-effectiveness of seven biologic disease-modifying antirheumatic drugs (bDMARDs) compared with each other and conventional disease-modifying antirheumatic drugs (cDMARDs). The decision problem was divided into those patients who were cDMARD naive and those who were cDMARD experienced; whether a patient had severe or moderate to severe disease; and whether or not an individual could tolerate methotrexate (MTX). DATA SOURCES The following databases were searched: MEDLINE from 1948 to July 2013; EMBASE from 1980 to July 2013; Cochrane Database of Systematic Reviews from 1996 to May 2013; Cochrane Central Register of Controlled Trials from 1898 to May 2013; Health Technology Assessment Database from 1995 to May 2013; Database of Abstracts of Reviews of Effects from 1995 to May 2013; Cumulative Index to Nursing and Allied Health Literature from 1982 to April 2013; and TOXLINE from 1840 to July 2013. Studies were eligible for inclusion if they evaluated the impact of a bDMARD used within licensed indications on an outcome of interest compared against an appropriate comparator in one of the stated population subgroups within a randomised controlled trial (RCT). Outcomes of interest included American College of Rheumatology (ACR) scores and European League Against Rheumatism (EULAR) response. Interrogation of Early Rheumatoid Arthritis Study (ERAS) data was undertaken to assess the Health Assessment Questionnaire (HAQ) progression while on cDMARDs. METHODS Network meta-analyses (NMAs) were undertaken for patients who were cDMARD naive and for those who were cDMARD experienced. These were undertaken separately for EULAR and ACR data. Sensitivity analyses were undertaken to explore the impact of including RCTs with a small proportion of bDMARD experienced patients and where MTX exposure was deemed insufficient. A mathematical model was constructed to simulate the experiences of hypothetical patients. The model was based on EULAR response as this is commonly used in clinical practice in England. Observational databases, published literature and NMA results were used to populate the model. The outcome measure was cost per quality-adjusted life-year (QALY) gained. RESULTS Sixty RCTs met the review inclusion criteria for clinical effectiveness, 38 of these trials provided ACR and/or EULAR response data for the NMA. Fourteen additional trials contributed data to sensitivity analyses. There was uncertainty in the relative effectiveness of the interventions. It was not clear whether or not formal ranking of interventions would result in clinically meaningful differences. Results from the analysis of ERAS data indicated that historical assumptions regarding HAQ progression had been pessimistic. The typical incremental cost per QALY of bDMARDs compared with cDMARDs alone for those with severe RA is > £40,000. This increases for those who cannot tolerate MTX (£50,000) and is > £60,000 per QALY when bDMARDs were used prior to cDMARDs. Values for individuals with moderate to severe RA were higher than those with severe RA. Results produced using EULAR and ACR data were similar. The key parameter that affected the results is the assumed HAQ progression while on cDMARDs. When historic assumptions were used typical incremental cost per QALY values fell to £38,000 for those with severe disease who could tolerate MTX. CONCLUSIONS bDMARDs appear to have cost per QALY values greater than the thresholds stated by the National Institute for Health and Care Excellence for interventions to be cost-effective. Future research priorities include: the evaluation of the long-term HAQ trajectory while on cDMARDs; the relationship between HAQ direct medical costs; and whether or not bDMARDs could be stopped once a patient has achieved a stated target (e.g. remission). STUDY REGISTRATION This study is registered as PROSPERO CRD42012003386. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Treatments for Hyperemesis Gravidarum and Nausea and Vomiting in Pregnancy: A Systematic Review

OBJECTIVES To assess whether thrombophilia testing following a venous thrombotic event is clinically effective and cost-effective in the management of thrombosis compared with no testing for thrombophilia. DATA SOURCES Major electronic databases were searched from September to November 2006. REVIEW METHODS A systematic review of the clinical effectiveness and cost-effectiveness literature was undertaken according to standard methods. A discrete event simulation model was constructed to assess the cost-effectiveness of changing the standard 3-month duration of warfarin treatment to 10 years, 20 years or lifelong. RESULTS No clinical studies were identified that met the inclusion criteria for the systematic review. Further literature searches and clinical opinion were therefore used to inform the cost-effectiveness analysis. Thrombophilia testing in patients with pulmonary embolism (PE) had an estimated mean cost per quality-adjusted life-year (QALY) of below 20,000 pounds regardless of sex or age. In patients with a previous deep vein thrombosis (DVT), thrombophilia testing had an estimated mean cost per QALY of below 20,000 pounds in men aged 69 years or less and in women aged 49 years or less. The estimated duration of warfarin treatment (lifelong, 20 years, 10 years or no extended treatment) that was most cost-effective is presented for each age, sex, initial venous thromboembolism (VTE) event and type of thrombophilia. CONCLUSIONS In terms of determining the duration of anticoagulation management, scenarios were found in which the cost per QALY of thrombophilia testing was below 20,000 pounds. However, these results are subject to great uncertainty, largely because of lack of knowledge about the increased risk of recurrence with each type of thrombophilia. Results are influenced by the fact that men have a greater risk of recurrence than women and by the fact that the frequency of adverse events associated with warfarin treatment increases with age. Further research, for example on the likely sensitivity and specificity of the tests for specific types of thrombophilia, is needed to reduce the uncertainty associated with these results. Studies comparing patients with VTE tested for thrombophilia with those whose risk assessment was based on personal and family history of thrombosis would also be beneficial.