Human health impacts of exposure to phthalate plasticizers: An overview of reviews.

In this review of reviews, we overview the current global body of available evidence from structured reviews of epidemiological studies that explore human health outcomes associated with exposure to phthalates (chemical plasticisers commonly found in plastics). We found robust evidence for an association with lower semen quality, neurodevelopment and risk of childhood asthma, and moderate to robust evidence for impact on anogenital distance in boys. We identified moderate evidence for an association between phthalates/metabolites and low birthweight, endometriosis, decreased testosterone, ADHD, Type 2 diabetes and breast/uterine cancer. There was some evidence for other outcomes including anofourchette distance, fetal sex hormones, pre-term birth, lower antral follicle count, reduced oestrodiol, autism, obesity, thyroid function and hearing disorders. We found no reviews of epidemiological human studies on the impact of phthalates from recycled plastics on human health. We recommend that future research should use urine samples as exposure measures, consider confounders in analyses and measure impacts on female reproductive systems. Our findings align with emerging research indicating that health risks can occur at exposure levels below the "safe dose" levels set out by regulators, and are of particular concern given potential additive or synergistic "cocktail effects" of chemicals. This raises important policy and regulatory issues for identifying and controlling plastics and health related impacts and highlights a need for more research into substances of concern entering plastics waste streams via recycling.

What is the best way of delivering virtual nature for improving mood? An experimental comparison of high definition TV, 360° video, and computer generated virtual reality.

Exposure to 'real' nature can increase positive affect and decrease negative affect, but direct access is not always possible, e.g. for people in health/care settings who often experience chronic boredom. In these settings 'virtual' forms of nature may also have mood-related benefits (e.g. reducing boredom) but it has been difficult to separate effects of nature content from those of delivery mode. The present laboratory-based study explored whether exposure to three different delivery modes of virtual nature could reduce negative affect (including boredom) and/or increase positive affect. Adult volunteer participants (n = 96) took part in a boredom induction task (to simulate the emotional state of many people in health/care settings) before being randomly assigned to view/interact with a virtual underwater coral reef in one of three experimental conditions: (a) 2D video viewed on a high-definition TV screen; (b) 3600 video VR (360-VR) viewed via a head mounted display (HMD); or (c) interactive computer-generated VR (CG-VR), also viewed via a HMD and interacted with using a hand-held controller. Visual and auditory content was closely matched across conditions with help from the BBC's Blue Planet II series team. Supporting predictions, virtual exposure to a coral reef reduced boredom and negative affect and increased positive affect and nature connectedness. Although reductions in boredom and negative affect were similar across all three conditions, CG-VR was associated with significantly greater improvements in positive affect than TV, which were mediated by greater experienced presence and increases in nature connectedness. Results improve our understanding of the importance of virtual nature delivery mode and will inform studies in real care settings.

Patients' experiences of deep brain stimulation for Parkinson's disease: a qualitative systematic review and synthesis.

OBJECTIVE: To review and synthesise qualitative research studies that have explored patients' experience of deep brain stimulation (DBS) in advanced Parkinson's disease (PD). DESIGN: Systematic review and meta-synthesis of 7 original papers, using metaethnography. SETTING: Studies conducted in Denmark, France and Sweden. PARTICIPANTS: 116 patients who had undergone DBS and 9 spouses of patients. RESULTS: Prior to surgery, the experience of advancing PD is one of considerable loss and a feeling of loss of control. There are significant hopes for what DBS can bring. Following surgery, a sense of euphoria is described by many, although this does not persist and there is a need for significant transitions following this. We suggest that normality as a concept is core to the experience of DBS and that a sense of control may be a key condition for normality. Experience of DBS for patients and spouses, and of the transitions that they must undertake, is influenced by their hopes of what surgery will enable them to achieve, or regain (ie, a new normality). CONCLUSIONS: There is a need for further qualitative research to understand the nature of these transitions to inform how best patients and their spouses can be supported by healthcare professionals before, during and after DBS. In assessing the outcomes of DBS and other treatments in advanced PD, we should consider how to capture holistic concepts such as normality and control. Studies that examine the outcomes of DBS require longer term follow-up.

Systematic review of the psychological consequences of false-positive screening mammograms.

BACKGROUND: In the UK, women aged 50-73 years are invited for screening by mammography every 3 years. In 2009-10, more than 2.24 million women in this age group in England were invited to take part in the programme, of whom 73% attended a screening clinic. Of these, 64,104 women were recalled for assessment. Of those recalled, 81% did not have breast cancer; these women are described as having a false-positive mammogram. OBJECTIVE: The aim of this systematic review was to identify the psychological impact on women of false-positive screening mammograms and any evidence for the effectiveness of interventions designed to reduce this impact. We were also looking for evidence of effects in subgroups of women. DATA SOURCES: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Health Management Information Consortium, Cochrane Central Register for Controlled Trials, Cochrane Database of Systematic Reviews, Centre for Reviews and Dissemination (CRD) Database of Abstracts of Reviews of Effects, CRD Health Technology Assessment (HTA), Cochrane Methodology, Web of Science, Science Citation Index, Social Sciences Citation Index, Conference Proceedings Citation Index-Science, Conference Proceeding Citation Index-Social Science and Humanities, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Sociological Abstracts, the International Bibliography of the Social Sciences, the British Library's Electronic Table of Contents and others. Initial searches were carried out between 8 October 2010 and 25 January 2011. Update searches were carried out on 26 October 2011 and 23 March 2012. REVIEW METHODS: Based on the inclusion criteria, titles and abstracts were screened independently by two reviewers. Retrieved papers were reviewed and selected using the same independent process. Data were extracted by one reviewer and checked by another. Each included study was assessed for risk of bias. RESULTS: Eleven studies were found from 4423 titles and abstracts. Studies that used disease-specific measures found a negative psychological impact lasting up to 3 years. Distress increased with the level of invasiveness of the assessment procedure. Studies using instruments designed to detect clinical levels of morbidity did not find this effect. Women with false-positive mammograms were less likely to return for the next round of screening [relative risk (RR) 0.97; 95% confidence interval (CI) 0.96 to 0.98] than those with normal mammograms, were more likely to have interval cancer [odds ratio (OR) 3.19 (95% CI 2.34 to 4.35)] and were more likely to have cancer detected at the next screening round [OR 2.15 (95% CI 1.55 to 2.98)]. LIMITATIONS: This study was limited to UK research and by the robustness of the included studies, which frequently failed to report quality indicators, for example failure to consider the risk of bias or confounding, or failure to report participants' demographic characteristics. CONCLUSIONS: We conclude that the experience of having a false-positive screening mammogram can cause breast cancer-specific psychological distress that may endure for up to 3 years, and reduce the likelihood that women will return for their next round of mammography screening. These results should be treated cautiously owing to inherent weakness of observational designs and weaknesses in reporting. Future research should include a qualitative interview study and observational studies that compare generic and disease-specific measures, collect demographic data and include women from different social and ethnic groups.

Dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia: systematic reviews and economic analyses.

BACKGROUND: Nilotinib and dasatinib are now being considered as alternative treatments to imatinib as a first-line treatment of chronic myeloid leukaemia (CML). OBJECTIVE: This technology assessment reviews the available evidence for the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of Philadelphia chromosome-positive CML. DATA SOURCES: Databases [including MEDLINE (Ovid), EMBASE, Current Controlled Trials, ClinicalTrials.gov, the US Food and Drug Administration website and the European Medicines Agency website] were searched from search end date of the last technology appraisal report on this topic in October 2002 to September 2011. REVIEW METHODS: A systematic review of clinical effectiveness and cost-effectiveness studies; a review of surrogate relationships with survival; a review and critique of manufacturer submissions; and a model-based economic analysis. RESULTS: Two clinical trials (dasatinib vs imatinib and nilotinib vs imatinib) were included in the effectiveness review. Survival was not significantly different for dasatinib or nilotinib compared with imatinib with the 24-month follow-up data available. The rates of complete cytogenetic response (CCyR) and major molecular response (MMR) were higher for patients receiving dasatinib than for those with imatinib for 12 months' follow-up (CCyR 83% vs 72%, p < 0.001; MMR 46% vs 28%, p < 0.0001). The rates of CCyR and MMR were higher for patients receiving nilotinib than for those receiving imatinib for 12 months' follow-up (CCyR 80% vs 65%, p < 0.001; MMR 44% vs 22%, p < 0.0001). An indirect comparison analysis showed no difference between dasatinib and nilotinib for CCyR or MMR rates for 12 months' follow-up (CCyR, odds ratio 1.09, 95% CI 0.61 to 1.92; MMR, odds ratio 1.28, 95% CI 0.77 to 2.16). There is observational association evidence from imatinib studies supporting the use of CCyR and MMR at 12 months as surrogates for overall all-cause survival and progression-free survival in patients with CML in chronic phase. In the cost-effectiveness modelling scenario, analyses were provided to reflect the extensive structural uncertainty and different approaches to estimating OS. First-line dasatinib is predicted to provide very poor value for money compared with first-line imatinib, with deterministic incremental cost-effectiveness ratios (ICERs) of between £256,000 and £450,000 per quality-adjusted life-year (QALY). Conversely, first-line nilotinib provided favourable ICERs at the willingness-to-pay threshold of £20,000-30,000 per QALY. LIMITATIONS: Immaturity of empirical trial data relative to life expectancy, forcing either reliance on surrogate relationships or cumulative survival/treatment duration assumptions. CONCLUSIONS: From the two trials available, dasatinib and nilotinib have a statistically significant advantage compared with imatinib as measured by MMR or CCyR. Taking into account the treatment pathways for patients with CML, i.e. assuming the use of second-line nilotinib, first-line nilotinib appears to be more cost-effective than first-line imatinib. Dasatinib was not cost-effective if decision thresholds of £20,000 per QALY or £30,000 per QALY were used, compared with imatinib and nilotinib. Uncertainty in the cost-effectiveness analysis would be substantially reduced with better and more UK-specific data on the incidence and cost of stem cell transplantation in patients with chronic CML. FUNDING: The Health Technology Assessment Programme of the National Institute for Health Research.

Ofatumumab for the treatment of chronic lymphocytic leukaemia in patients who are refractory to fludarabine and alemtuzumab: a critique of the submission from GSK.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of ofatumumab for the treatment of refractory chronic lymphocytic leukaemia (CLL), based upon the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence included one study: a non-randomised, single-arm study. Two other studies were identified but both were non-comparative and provided evidence for therapies other than ofatumumab. For this reason these studies were not discussed in full in the main body of the submission. In the Hx-CD20-406 study, the overall response rate was 58% (99% confidence interval 40% to 74%, p < 0.001). Complete resolution of constitutional symptoms and improved performance status occurred in 57% of patients. Median progression-free survival (PFS) and overall survival (OS) times were 5.7 and 13.7 months, respectively. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. The MS concluded that ofatumumab provides a new, effective and well-tolerated therapy for patients with CLL who are refractory to both fludarabine and alemtuzumab [double refractory (DR)]. The ERG undertook a critical appraisal of the submission. The ERG had a number of concerns regarding the manufacturer's estimates of effectiveness based on evidence from a single-arm, non-randomised study. An 'area-under-the-curve' or 'partitioned-survival' model was used to project expected clinical and economic outcomes for patients with DR CLL who were assumed to receive ofatumumab or best supportive care (BSC). The model had a three-state structure: 'alive pre-progression', 'alive post progression' and 'dead'. Overall, the modelling approach is reasonable given the limited evidence available for the drug in the patient population under review. However, a number of uncertainties were identified in the economic evaluation; for example, the BSC arm used data from patients in the Hx-CD20-406 study who did not respond to ofatumumab treatment - 'non-responders' - and the ofatumumab arm used data from all of those treated in the Hx-CD20-406 study. Further uncertainty arose regarding the choice of utilities, the omission of 17p and 11q chromosomal deletions as factors in the Cox proportional hazards models for PFS and OS, and the omission of the costs of drugs in progressive disease. It was felt that these factors biased cost-effectiveness in favour of ofatumumab. When revisions were made to the assumptions in the model based on the ERG's review of the published and submitted evidence, the revised base-case incremental cost-effectiveness ratio for ofatumumab increased to £ 81,500 per quality-adjusted life-year. The final appraisal determination was issued by NICE in September 2010 (www.nice.org.uk/nicemedia/live/12264/50758/50758.pdf).

The harmful health effects of recreational ecstasy: a systematic review of observational evidence.

OBJECTIVES: To investigate the harmful health effects of taking ecstasy (3,4-methylenedioxymethamphetamine, MDMA) for recreational purposes. DATA SOURCES: MEDLINE, EMBASE, PsycINFO and Web of Knowledge were searched. Additional information on deaths was collected from the General Mortality Register (GMR) and the Special Mortality Register collated by the National Programme on Substance Abuse Deaths (np-SAD). REVIEW METHODS: Studies were categorised according to design, with systematic research syntheses (Level I evidence) the most valid and least open to bias. Where Level I evidence was not available, controlled observational studies (Level II evidence) were systematically reviewed. If neither Level I nor Level II evidence was available, uncontrolled case series and case reports (Level III evidence) were systematically surveyed. Data were extracted by one reviewer and a sample checked by a second. The heterogeneity of Level II evidence was addressed by undertaking stratified analyses for current and former ecstasy users and comparing them either with control groups using other illegal drugs but not ecstasy (polydrug controls) or with controls naïve to illegal drugs (drug-naïve controls). Statistical heterogeneity was minimised by using a random-effects model throughout and investigated using study-level regression analysis (metaregression). RESULTS: Five Level I syntheses were identified; for each it was difficult to ascertain the exact methods adopted and evidence included. Small but significant deficits for ecstasy users compared to controls were reported in areas relating to attention, memory, psychomotor speed, executive systems functioning, and self-reported depressive symptoms. Data from Level II studies were directly pooled for seven individual outcomes, suggesting that ecstasy users performed worse than controls on common measures of immediate and delayed verbal recall (RAVLT, RBMT, digit span). No difference was seen in IQ (NART). The 915 outcome measures identified in Level II studies were analysed in broad domains: immediate and delayed verbal and visual memory, working memory, two measures of attention, three measures of executive function, perceptual organisation, self-rated depression, memory and anxiety, and impulsivity measured objectively and subjectively. Ecstasy users performed significantly worse than polydrug controls in 13/16 domains and significantly worse than drug-naïve controls in 7/12 domains for which sufficient data were available. The largest, most consistent exposure effects were seen in meta-analyses of memory (especially verbal and working memory, with less marked effects seen in visual memory). Former ecstasy users frequently showed deficits that matched or exceeded those seen amongst current users. At aggregate level, the effects do not appear to be dose-related, but are variably confounded by other drug use, particularly alcohol. Of Level III evidence, in the 10 years to 2006, the np-SAD and the GMR recorded an average of around 50 drug-related deaths per year involving ecstasy; it was the sole drug implicated in around 10 cases per year. Retrospective case series, based on hospital emergency department records, reported a death rate of 0-2% from emergency admissions related to ecstasy. Two major syndromes are most commonly reported as the immediate cause of death in fatal cases: hyperthermia and hyponatraemia. CONCLUSIONS: A broad range of relatively low-quality literature suggests that recreational use of ecstasy is associated with significant deficits in neurocognitive function (particularly immediate and delayed verbal memory) and increased psychopathological symptoms. The clinical significance of the exposure effect in individual cases will be variable but, on average, deficits are likely to be relatively small. Ecstasy is associated with a range of acute harms but appears to be a rare cause of death in isolation.

Methods for siRNA-mediated reduction of mRNA and protein expression in human placental explants, isolated primary cells and cell lines.

The use of RNA interference (RNAi) to deplete individual proteins from cells or tissue has revolutionised our ability to characterise gene function. The placenta is an attractive target for studies in which the role of specific proteins can be compared with cell culture models and explanted villous tissue where physiological function can be maintained ex vivo. In this study, we compared a variety of commercially available reagents and approaches to define methods for efficient delivery of siRNA to placental cells. Protocols optimised using fluorescently-labelled siRNA were subsequently tested using siRNA sequences that target placental alkaline phosphatase (PLAP), chosen because of its high abundance in trophoblast. mRNA abundance was assayed using qRT-PCR, and the effect on protein was examined using immunolocalisation. We report that different protocols are required for BeWo choriocarcinoma cells (nucleofection), primary cytotrophoblast cells (lipid-based transfection) and villous tissue explants (nucleofection). The results provide guidelines for optimal siRNA-mediated knockdown in these three models of the human placenta.

Surveillance of Barrett's oesophagus: is it worthwhile?

OBJECTIVE: To assess the cost-effectiveness of surveillance of Barrett's oesophagus. DESIGN: Cost-utility model. SETTING: UK NHS. PATIENTS: One thousand 55-year-old men with Barrett's oesophagus. INTERVENTION: Surveillance programme: endoscopy and biopsy at 3 yearly intervals for non-dysplastic Barrett's oesophagus; low-grade dysplasia yearly; high grade-dysplasia 3 monthly. OUTCOME MEASURES: Incremental cost-effectiveness ratio, expected value of perfect information. RESULTS: Non-surveillance dominated surveillance (i.e. cost less and conferred more benefit), but there was substantial uncertainty around many of the model inputs. Probabilistic analyses showed that non-surveillance cost less and conferred more benefit in 75% of model runs. Surveillance was cost-effective at usual levels of willingness to pay in 11% of runs. For people with Barrett's oesophagus in England and Wales, a value of pound6.5 million is placed on acquiring perfect information about surveillance of Barrett's oesophagus. CONCLUSIONS: The PenTAG cost-utility model suggests that surveillance programmes do more harm than good.

The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical and cost-effectiveness of adjuvant carmustine wafers (BCNU-W) and also of adjuvant and concomitant temozolomide (TMZ), compared with surgery with radiotherapy. DATA SOURCES: Electronic databases were searched up to August 2005. REVIEW METHODS: Included trials were critically appraised for key elements of internal and external validity. Relevant data were extracted and a narrative synthesis of the evidence produced. Where possible, data on absolute survival at a fixed time point were meta-analysed using a random effects model. A Markov (state transition) model was developed to assess the cost-utility of the two interventions. The model compared BCNU-W or TMZ separately with current standard treatment with surgery and radiotherapy. The simulated cohort had a mean age of 55 years and was modelled over 5 years. RESULTS: Two randomised controlled trials (RCTs) (n = 32, n = 240) and two observational studies of BCNU-W compared with placebo wafers as adjuvant therapy to surgery and radiotherapy for newly diagnosed high-grade glioma were identified. All the studies were in adults and provided data on 193 patients who had received BCNU-W. The RCT findings excluded under 65-year-olds and those with a Karnofsky Performance Status of less than 60. The largest multi-centre RCT suggested a possible survival advantage with BCNU-W among a cohort of patients with grade III and IV tumours, adding a median of 2.3 months [95% confidence interval (CI) -0.5 to 5.1]. However, analysis using per-protocol, unstratified methods shows this difference to be not statistically significant (HR 0.77, 95% CI 0.57 to 1.03, p = 0.08). Long-term follow-up suggests a significant survival advantage using unstratified analysis. No difference in progression-free survival (PFS) was demonstrated. Subgroup analysis of those with grade IV tumours also showed no significant survival advantage with BCNU-W [hazard ratio (HR) 0.82, 95% CI 0.55 to 1.11, p = 0.20, unstratified analysis]. It is estimated that the cost of surgery and radiotherapy, with follow-up, treatment of adverse effects and end of life care is around 17,000 pounds per patient. Treatment with BCNU-W adds an additional 6600 pounds. Across the modelled cohort of 1000 patients, use of BCNU-W costs an additional 6.6 million pounds and confers an additional 122 quality-adjusted life-years (QALYs). On average, that is 6600 pounds per patient for 0.122 QALYs (6.3 quality-adjusted life-weeks). The base-case incremental cost-effectiveness ratio (ICER) is 54,500 pounds/QALY. In probabilistic sensitivity analyses, BCNU-W was not cost-effective in 89% of the simulations assuming a willingness to pay threshold of 30,000 pounds/QALY. In 15% of simulations, BCNU-W was dominated (i.e. did more harm than good, conferring fewer QALYs at greater cost). The cost-effectiveness acceptability curve (CEAC) suggests that it is very unlikely to be the most cost-effective option at normal levels of willingness to pay (11% probability at 30,000 pounds/QALY), only becoming likely to be the most cost-effective option at much higher levels of willingness to pay (50% probability at 55,000 pounds/QALY). Two RCTs (n = 130, n = 573) and two observational studies were included, giving evidence for 429 adult patients receiving TMZ. Currently, TMZ is licensed for use in those with newly diagnosed grade IV gliomas only. The RCTs excluded those with lower performance status and, in the larger RCT, those older than 70 years. TMZ provides a small but statistically significant median survival benefit of 2.5 months (95% CI 2.0 to 3.8), giving an HR of 0.63 (95% CI 0.52 to 0.75, p < 0.001). At 2 years, 26.5% of patients treated with TMZ were alive compared with 10.4% of those in the control arm. Median PFS is also enhanced with TMZ, giving a median 1.9 months' advantage (95% CI 1.4 to 2.7, p < 0.001). No analysis of the subgroup of patients with confirmed grade IV tumours was undertaken. Subgroup analysis of patients by O6-methylguanine-DNA methyltransferase (MGMT) activity showed a significant treatment advantage for those with reduced MGMT activity but not for those with normal activity, although this analysis was based on a selected sample of patients and the test used has proved difficult to replicate. A median gain of 6.4 (95% CI 4.4 to 9.5) more life-months is seen with TMZ among those with reduced MGMT, giving an HR of 0.51 (p < 0.007). PFS is increased by a median of 4.4 months (95% CI 1.2 to 6.3), giving an HR of 0.48 (p = 0.001). The model shows a cost per patient for being treated with surgery, radiotherapy and including adverse effects of treatment and end of life care of around 17,000 pounds per patient. TMZ in the adjuvant and concomitant phase adds an additional cost of around 7800 pounds. Across the modelled cohort of 1000 patients, use of TMZ costs an additional 7.8 million pounds and confers an additional 217 QALYs. For the average patient this is 7800 pounds for an additional 0.217 QALYs (11 quality-adjusted life-weeks). The base-case ICER is 36,000 pounds/QALY. Probabilistic sensitivity analyses shows that TMZ was not cost-effective in 77% of the simulations. The CEAC suggests that there is a 23% chance that TMZ is the most cost-effective option at a willingness to pay level of 30,000 pounds/QALY, rising to be more cost-effective than no TMZ at slightly higher levels (50% probability at 35,000 pounds/QALY). CONCLUSIONS: BCNU-W has not been proven to confer a significant advantage in survival for patients with grade III tumours when treated with the drug, compared with placebo. There does not appear to be a survival advantage for patients with grade IV tumours. No increase in PFS has been shown. Limited evidence suggests a small but significant advantage in both overall survival and PFS with TMZ among a mixed population with grade IV and grade III (7-8%) tumours. However, it remains unclear whether this is true in grade IV tumours alone. On the basis of best available evidence, the authors consider that neither BCNU-W nor TMZ is likely to be considered cost-effective by NHS decision-makers. However, data for the model were drawn from limited evidence of variable quality. Tumour type is clearly important in assessing patient prognosis with different treatments. Grade IV tumours are commonest and appear to have least chance of response. There were too few grade III tumours included to carry out a formal assessment, but they appear to respond better and drive results for both drugs. Future use of genetic and biomarkers may help identify subtypes which will respond, but current licensing indications do not specify these. Further research is suggested into the effectiveness of these drugs, and also into areas such as genetic markers, chemotherapy regimens, patient and carer quality of life, and patient views on survival advantages vs treatment disadvantages.

Topical pimecrolimus for eczema.

BACKGROUND: Pimecrolimus was developed as an alternative to topical corticosteroids for treating eczema (atopic dermatitis) but its efficacy and safety compared with existing treatments remains unclear. OBJECTIVES: To assess the effects of topical pimecrolimus for treating eczema. SEARCH STRATEGY: We searched the Cochrane Skin Group Specialised Register (to October 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2006), MEDLINE (from 2003 to October 2006), and EMBASE (from 2005 to October 2006). We also contacted researchers and manufacturers in the field. SELECTION CRITERIA: Randomised controlled trials of 1.0% topical pimecrolimus used twice daily compared against other topical comparators for treating eczema. DATA COLLECTION AND ANALYSIS: Two authors independently examined each retrieved study for eligibility and extracted data for efficacy, tolerability and safety. A random-effects model was used to estimate the pooled risk ratios (RRs) and 95% confidence intervals (95% CIs). MAIN RESULTS: We included 31 trials (8019 participants) in the analysis. In short-term (/=6 months), pimecrolimus was significantly better than vehicle in preventing flares (9 trials, 3091 participants, RR 1.47, 95% CI 1.32 to 1.64 at six months) and in improving quality of life. Pimecrolimus was significantly less effective than two topical corticosteroids, i.e. 0.1% triamcinolone acetonide for investigators' global assessment (1 trial, 658 participants, RR 0.75, 95% CI 0.67 to 0.83) and 0.1% betamethasone valerate for participants' global assessment (1 trial, 87 participants, RR 0.61, 95% CI 0.45 to 0.81) at three weeks. Pimecrolimus was also associated with significantly more overall withdrawals and skin burning. None of the trials reported on key adverse effects such as thinning of skin. Pimecrolimus was significantly less effective than 0.1% tacrolimus for investigators' global assessment at six weeks (RR 0.58, 95% CI 0.46 to 0.74) and led to more withdrawals due to lack of efficacy (RR 2.37, 95% CI 1.10 to 5.08) based on two trials involving 639 participants, but there was no significant difference in proportions of participants experiencing any adverse events. AUTHORS' CONCLUSIONS: Topical pimecrolimus is less effective than moderate and potent corticosteroids and 0.1% tacrolimus. The therapeutic role of topical pimecrolimus is uncertain due to the absence of key comparisons with mild corticosteroids.

The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients on dialysis: a systematic review and economic evaluation.

OBJECTIVES: To establish the effectiveness and cost-effectiveness of cinacalcet for the treatment of secondary hyperparathyroidism (SHPT) for people on dialysis due to end-stage renal disease (ESRD). DATA SOURCES: Electronic databases were searched up to February 2006. REVIEW METHODS: Included randomised controlled trials (RCTs) on the clinical effectiveness of cinacalcet for SHPT in ESRD were critically appraised, had relevant data extracted and were summarised narratively. A Markov (state transition) model was developed that compared cinacalcet in addition to current standard treatment with phosphate binders and vitamin D to standard treatment alone. A simulated cohort of 1000 people aged 55 with SHPT was modelled until the whole cohort was dead. Incremental costs and quality-adjusted life-years (QALYs) were calculated. Extensive one-way sensitivity analysis was undertaken as well as probabilistic sensitivity analysis. RESULTS: Seven trials comparing cinacalcet plus standard treatment with placebo plus standard treatment were included in the systematic review. A total of 846 people were randomised to receive cinacalcet. Cinacalcet was more effective at meeting parathyroid hormone (PTH) target levels (40% vs 5% in placebo, p < 0.001). In those patients meeting PTH targets, 90% also experienced a reduction in calcium-phosphate product levels, compared with 1% in placebo. Significantly fewer people treated with cinacalcet were hospitalised for cardiovascular events, although no difference was seen in all-cause hospitalisation or mortality. Significantly fewer fractures and parathyroidectomies were also seen with cinacalcet. Findings on all patient-based clinical outcomes were based on small numbers. The authors' economic model estimated that, compared to standard treatment alone, cinacalcet in addition to standard care costs an additional 21,167 pounds and confers 0.34 QALYs (or 18 quality-adjusted weeks) per person. The incremental cost-effectiveness ratio (ICER) was 61,890 pounds/QALY. In most cases, even extreme adjustments to individual parameters did not result in an ICER below a willingness-to-pay threshold of 30,000 pounds/QALY with probabilistic analysis showing only 0.5% of simulations to be cost-effective at this threshold. Altering the assumptions in the model through using different data sources for the inputs produced a range of ICERs from 39,000 pounds to 92,000 pounds/QALY. CONCLUSIONS: Cinacalcet in addition to standard care is more effective than placebo plus standard care at reducing PTH levels without compromising calcium levels. However, there is limited information about the impact of this reduction on patient-relevant clinical outcomes. Given the short follow-up in the trials, it is unclear how data should be extrapolated to the long term. Together with the high drug cost, this leads to cinacalcet being unlikely to be considered cost-effective. Recommendations for future research include obtaining accurate estimates of the multivariate relationship between biochemical disruption in SHPT and long-term clinical outcomes.

A cost-utility analysis of pimecrolimus vs. topical corticosteroids and emollients for the treatment of mild and moderate atopic eczema.

BACKGROUND: Conventional treatments for atopic eczema include topical corticosteroids (TCS) and emollients. Pimecrolimus, an immunosuppressant, was licensed in the U.K. in 2003 as an alternative treatment of mild to moderate atopic eczema. OBJECTIVES: To assess the cost-utility of pimecrolimus as a treatment for mild and moderate atopic eczema when compared with conventional treatments which use TCS and emollients. METHODS: A Markov state-transition model was developed to represent the cyclical nature of atopic eczema and provide an economic analysis of cost-utility for treatment alternatives from the perspective of a third party payer (U.K. National Health Service). A range of methods was used to obtain data for transition probabilities, costs and quality of life. These included a systematic review of published effectiveness data, expert opinion, and a utility study conducted by the authors. Separate cohort analyses were modelled to distinguish between children and adult populations and between differing treatment patterns for facial and body eczema. One-way sensitivity analyses and probabilistic sensitivity analysis (using Monte-Carlo simulation) were performed. RESULTS: Baseline cost-utility outputs from the model show that, in all tested scenarios, TCS dominate pimecrolimus (i.e. TCS are both cheaper and more effective). However, the differences in benefits between treatments output by the model are very small. Sensitivity analyses highlight the importance of cost variations in pimecrolimus. Where pimecrolimus is compared with emollient only it is probably cost effective at a willingness-to-pay threshold of 30 000 UK pounds per quality-adjusted life year. CONCLUSIONS: There are likely to be few situations in which the use of pimecrolimus for the treatment of atopic eczema can be justified on economic grounds. Exceptions are likely to be in cases where TCS have been shown to be ineffective, unacceptable due to adverse events, or where a patient is unwilling to accept TCS treatment despite appropriate education and support and emollient alone is the alternative clinical option.

Surveillance of Barrett's oesophagus: exploring the uncertainty through systematic review, expert workshop and economic modelling.

OBJECTIVES: To assess what is known about the effectiveness, safety, affordability, cost-effectiveness and organisational impact of endoscopic surveillance in preventing morbidity and mortality from adenocarcinoma in patients with Barrett's oesophagus. In addition, to identify important areas of uncertainty in current knowledge for these programmes and to identify areas for further research. DATA SOURCES: Electronic databases up to March 2004. Experts in Barrett's oesophagus from the UK. REVIEW METHODS: A systematic review of the effectiveness of endoscopic surveillance of Barrett's oesophagus was carried out following methodological guidelines. Experts in Barrett's oesophagus from the UK were invited to contribute to a workshop held in London in May 2004 on surveillance of Barrett's oesophagus. Small group discussion, using a modified nominal group technique, identified key areas of uncertainty and ranked them for importance. A Markov model was developed to assess the cost-effectiveness of a surveillance programme for patients with Barrett's oesophagus compared with no surveillance and to quantify important areas of uncertainty. The model estimates incremental cost--utility and expected value of perfect information for an endoscopic surveillance programme compared with no surveillance. A cohort of 1000 55-year-old men with a diagnosis of Barrett's oesophagus was modelled for 20 years. The base case used costs in 2004 and took the perspective of the UK NHS. Estimates of expected value of information were included. RESULTS: No randomised controlled trials (RCTs) or well-designed non-randomised controlled studies were identified, although two comparative studies and numerous case series were found. Reaching clear conclusions from these studies was impossible owing to lack of RCT evidence. In addition, there was incomplete reporting of data particularly about cause of death, and changes in surveillance practice over time were mentioned but not explained in several studies. Three cost--utility analyses of surveillance of Barrett's oesophagus were identified, of which one was a further development of a previous study by the same group. Both sets of authors used Markov modelling and confined their analysis to 50- or 55-year-old white men with gastro-oesophageal reflux disease (GORD) symptoms. The models were run either for 30 years or to age 75 years. As these models are American, there are almost certainly differences in practice from the UK and possible underlying differences in the epidemiology and natural history of the disease. The costs of the procedures involved are also likely to be very different. The expert workshop identified the following key areas of uncertainty that needed to be addressed: the contribution of risk factors for the progression of Barrett's oesophagus to the development of high-grade dysplasia (HGD) and adenocarcinoma of the oesophagus; possible techniques for use in the general population to identify patients with high risk of adenocarcinoma; effectiveness of treatments for Barrett's oesophagus in altering cancer incidence; how best to identify those at risk in order to target treatment; whether surveillance programmes should take place at all; and whether there are clinical subgroups at higher risk of adenocarcinoma. Our Markov model suggests that the base case scenario of endoscopic surveillance of Barrett's oesophagus at 3-yearly intervals, with low-grade dysplasia surveyed yearly and HGD 3-monthly, does more harm than good when compared with no surveillance. Surveillance produces fewer quality-adjusted life-years (QALYs) for higher cost than no surveillance, therefore it is dominated by no surveillance. The cost per cancer identified approaches pound 45,000 in the surveillance arm and there is no apparent survival advantage owing to high recurrence rates and increased mortality due to more oesophagectomies in this arm. Non-surveillance continues to cost less and result in better quality of life whatever the surveillance intervals for Barrett's oesophagus and dysplastic states and whatever the costs (including none) attached to endoscopy and biopsy as the surveillance test. The probabilistic analyses assess the overall uncertainty in the model. According to this, it is very unlikely that surveillance will be cost-effective even at relatively high levels of willingness to pay. The simulation showed that, in the majority of model runs, non-surveillance continued to cost less and result in better quality of life than surveillance. At the population level (i.e. people with Barrett's oesophagus in England and Wales), a value of pound 6.5 million is placed on acquiring perfect information about surveillance for Barrett's oesophagus using expected value of perfect information (EVPI) analyses, if the surveillance is assumed to be relevant over 10 years. As with the one-way sensitivity analyses, the partial EVPI highlighted recurrence of adenocarcinoma of the oesophagus (ACO) after surgery and time taken for ACO to become symptomatic as particularly important parameters in the model. CONCLUSIONS: The systematic review concludes that there is insufficient evidence available to assess the clinical effectiveness of surveillance programmes of Barrett's oesophagus. There are numerous gaps in the evidence, of which the lack of RCT data is the major one. The expert workshop reflected these gaps in the range of topics raised as important in answering the question of the effectiveness of surveillance. Previous models of cost-effectiveness have most recently shown that surveillance programmes either do more harm than good compared with no surveillance or are unlikely to be cost-effective at usual levels of willingness to pay. Our cost--utility model has shown that, across a range of values for the various parameters that have been chosen to reflect uncertainty in the inputs, it is likely that surveillance programmes do more harm than good -- costing more and conferring lower quality of life than no surveillance. Probabilistic analysis shows that, in most cases, surveillance does more harm and costs more than no surveillance. It is unlikely, but still possible, that surveillance may prove to be cost-effective. The cost-effectiveness acceptability curve, however, shows that surveillance is unlikely to be cost-effective at either the 'usual' level of willingness to pay ( pound 20,000-30,000 per QALY) or at much higher levels. The expected value of perfect information at the population level is pound 6.5 million. Future research should target both the overall effectiveness of surveillance and the individual elements that contribute to a surveillance programme, particularly the performance of the test and the effectiveness of treatment for both Barrett's oesophagus and ACO. In addition, of particular importance is the clarification of the natural history of Barrett's oesophagus.

The effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation.

OBJECTIVES: To estimate the effectiveness and cost-effectiveness of dual-chamber pacemakers versus single-chamber atrial or single-chamber ventricular pacemakers in the treatment of bradycardia due to sick sinus syndrome (SSS) or atrioventricular block (AVB). DATA SOURCES: Electronic databases and relevant Internet sites. Contact with device manufacturers and experts in the field. REVIEW METHODS: A systematic review was carried out of randomised controlled trials (RCTs). The quality of selected studies was appraised using standard frameworks. Meta-analyses, using random effects models, were carried out where appropriate. Limited exploration of heterogeneity was possible. Critical appraisal of economic evaluations was carried out using two frameworks. A decision-analytic model was developed using a Markov approach, to estimate the cost-effectiveness of dual-chamber versus ventricular or atrial pacing over 5 and 10 years as cost per quality-adjusted life-year (QALY). Uncertainty was explored using one-way and probabilistic sensitivity analyses. RESULTS: The searches retrieved a systematic review of effectiveness and cost-effectiveness published in 2002, four parallel group RCTs and 28 cross-over trials. Dual-chamber pacing was associated with lower rates of atrial fibrillation, particularly in SSS, than ventricular pacing, and prevents pacemaker syndrome. Higher rates of atrial fibrillation were seen with dual-chamber pacing than with atrial pacing. Complications occurred more frequently in dual-chamber pacemaker insertion. The cost of a dual-chamber system, over 5 years, including cost of complications and subsequent clinical events in the population, was estimated to be around 7400 pounds. The overall cost difference between single and dual systems is not large over this period: around 700 pounds more for dual-chamber devices. The cost-effectiveness of dual-chamber compared with ventricular pacing was estimated to be around 8500 pounds per QALY in AVB and 9500 pounds in SSS over 5 years, and around 5500 pounds per QALY in both populations over 10 years. Under more conservative assumptions, the cost-effectiveness of dual-chamber pacing is around 30,000 pounds per QALY. The probabilistic sensitivity analysis showed that, under the base-case assumptions, dual-chamber pacing is likely to be considered cost-effective at levels of willingness to pay that are generally considered acceptable by policy makers. In contrast, atrial pacing may be cost-effective compared with dual-chamber pacing. CONCLUSIONS: Dual-chamber pacing results in small but potentially important benefits in populations with SSS and/or AVB compared with ventricular pacemakers. Pacemaker syndrome is a crucial factor in determining cost-effectiveness; however, difficulties in standardising diagnosis and measurement of severity make it difficult to quantify. Dual-chamber pacing is in common usage in the UK. Recipients are more likely to be younger. Insufficient evidence is currently available to inform policy on specific groups who may benefit most from pacing with dual-chamber devices. Further important research is underway. Outstanding research priorities include the economic evaluation of UKPACE studies of the classification, diagnosis and utility associated with pacemaker syndrome and evidence on the effectiveness of pacemakers in children.

The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.

OBJECTIVES: To consider the effectiveness and cost-effectiveness of pimecrolimus for mild to moderate atopic eczema and tacrolimus for moderate to severe atopic eczema compared with current standard treatment in adults and children. DATA SOURCES: Electronic databases. Experts and the manufacturers of these agents were also approached for information. REVIEW METHODS: The systematic review was carried out using standard methodological guidelines and a stringent quality assessment strategy. A state transition (Markov) model was developed to estimate cost--utility of tacrolimus and pimecrolimus separately, compared with current standard practice with topical corticosteroids, (a) as first-line treatment and (b) as second-line treatment. Pimecrolimus was also compared to emollients only. RESULTS: The pimecrolimus trial reports were of varying quality; however when compared with a placebo (emollient), pimecrolimus was found to be more effective and to provide quality of life improvements. There is very little evidence available about pimecrolimus compared with topical corticosteroids. Compared with a placebo (emollient), both 0.03% and 0.1% tacrolimus were found to be more effective. Compared with a mild corticosteroid, 0.03% tacrolimus is more effective in children as measured by a 90% or better improvement in the Physician's Global Evaluation (PGE). Compared with potent topical corticosteroids, no significant difference in effectiveness is seen with 0.1% tacrolimus as measured by a 75% or greater improvement in the PGE. Minor application site adverse effects are common with tacrolimus. However, this did not lead to increased rates of withdrawal from treatment in trial populations. The PenTag economic model demonstrates a large degree of uncertainty, which was explored in both deterministic and stochastic analyses. This is the case for the cost-effectiveness of pimecrolimus and tacrolimus in first- or second-line use compared with topical steroids. In all cases immunosuppressant regimes were estimated to be more costly than alternatives and differences in benefits to be small and subject to considerable uncertainty. CONCLUSIONS: There is limited evidence from a small number of randomised controlled trials (RCTs) that pimecrolimus is more effective than placebo treatment in controlling mild to moderate atopic eczema. Although greater than for pimecrolimus, the evidence base for tacrolimus in moderate to severe atopic eczema is also limited. At both 0.1% and 0.03% potencies, tacrolimus appears to be more effective than the placebo treatment and mild topical corticosteroids. However, these are not the most clinically relevant comparators. Compared with potent topical corticosteroids, no significant difference was shown. Short-term adverse effects with both immunosuppressants are relatively common, but appear to be mild. Experience of long-term use of the agents is lacking so the risk of rare but serious adverse effects remains unknown. No conclusions can be confidently drawn about the cost-effectiveness of pimecrolimus or tacrolimus compared with active topical corticosteroid comparators. Areas for further research should focus on the effectiveness and safety of the treatments through good-quality RCTs and further economic analysis.

Do the findings of case series studies vary significantly according to methodological characteristics?

OBJECTIVES: To review the use of case series in National Institute for Clinical Excellence (NICE) Health Technology Assessment (HTA) reports, to review systematically the methodological literature for papers relating to the validity of aspects of case series design, and to investigate characteristics and findings of case series using examples from the UK's Health Technology Assessment programme. DATA SOURCES: Electronic databases. NICE website. Reports produced as part of the UK's HTA programme. REVIEW METHODS: NICE HTAs that used information from case series studies were obtained from the NICE website and a range of quality criteria applied. Searches of electronic databases, handsearched journals and the bibliographies of papers were made in order to find studies that assessed aspects of case series design, analysis or quality in relation to study validity. Hypotheses relating to the design of case series studies were developed and empirically investigated using four case examples from existing reports produced as part of the UK's HTA programme (functional endoscopic sinus surgery for nasal polyps, spinal cord stimulation for chronic back pain, percutaneous transluminal coronary angioplasty and coronary artery bypass grafting for chronic angina). Analysis was undertaken comparing studies within each review. RESULTS: There was no consensus on which case series to include in HTAs, how to use them or how to assess their quality, despite them being used in 30% of NICE HTAs. No previous studies empirically investigating methodological characteristics of case series were found. However, it is possible that the search strategy failed to find relevant studies. Poor reporting of case series characteristics severely constrained analysis and there were insufficient data to investigate all the hypotheses. Findings were not consistent across the different topics and were subject to considerable uncertainty. All the examples in our analysis were surgical interventions, which are prone to additional confounding factors due to difficulties of standardisation compared with drug treatment. Our findings may not be generalisable outside the interventions studied. The case series reports included generally exhibited poor reporting of methodological characteristics. This constrained our analysis. The use of several methods of analysis has led to apparently discrepant results. Given the number of analysis performed, the usual level of significance (p = 0.05) should be viewed with caution. The most important limitation of this study is the small number of cases on which the findings are based. The results are therefore tentative and should be viewed with caution. CONCLUSIONS: Case series are incorporated in a significant proportion of health technology assessments. Quality criteria have been used to appraise the quality of case series and decide on their inclusion in reviews of studies using this design. In this small series of case studies drawn from HTAs carried out for the NHS HTA programme, little evidence was found to support the use of many of the factors included in quality assessment tools. Importantly, no relationship was found between study size and outcome across the four examples studied. Isolated examples of a potentially important relationship between other methodological factors and outcome were shown, such as blinding of outcome measurement, but these were not shown consistently across the small number of examples studied. This study is based on a very small sample of studies and should therefore be considered as exploratory. Further investigation of the relationship between methodological features and outcome is justified given the frequency of use of case series in health technology assessments. Further research into the methodological features of case series and their outcome is justified in a wider sample of technologies and larger sets of case series. Value of information analyses including case series could be explored. Further exploration of the differences between case series and randomised controlled trial results, preferably using registry or comprehensive case series data, would be valuable.

Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: a systematic review and economic analysis.

OBJECTIVES: To evaluate the effectiveness of imatinib as first-line treatment for chronic myeloid leukaemia (CML) compared with interferon-alpha (IFN-alpha), hydroxyurea and bone marrow transplantation (BMT), and the cost-effectiveness of imatinib compared with IFN-alpha and hydroxyurea. DATA SOURCES: Electronic databases. REVIEW METHODS: Selected studies and full-text articles were screened and rigorously selected. Survival was the key outcome measure. Surrogate outcome measures included haematological (blood) response and cytogenetic (bone marrow) response (CR). As no published cost-effectiveness studies were found that compared imatinib and IFN-alpha, an independent Markov model was constructed and this was compared with models submitted to the National Institute for Clinical Excellence by the manufacturer of imatinib. RESULTS: Intention-to-treat analysis showed that imatinib was associated with complete CR at 12 months follow-up of 68% compared with 20% for the IFN-alpha plus Ara-C group. The estimated proportion of people taking imatinib who had not progressed to accelerated or blast phases at 12 months was 98.5%, and 93.1% for IFN-alpha plus Ara-C. Overall survival was not statistically significantly different. Withdrawal due to side-effects was 2% for imatinib and 5.6% for IFN-alpha plus Ara-C. Cross-over due to intolerance was 0.7% and 22.8% for imatinib and for IFN-alpha plus Ara-C, respectively. Quality of life was better in the imatinib group than the IFN-alpha group when assessed at 1, 3 and 6 months. Median survival across the four IFN-alpha versus hydroxyurea studies was 66 and 56.2 months, respectively. Median complete CR was 6% for IFN-alpha and 0 for hydroxyurea. Median withdrawal due to side-effects was 24% and 4% for IFN-alpha and hydroxyurea, respectively. Four out of the five studies comparing BMT and IFN-alpha showed a long-term survival advantage for BMT over IFN-alpha, but a short-term disadvantage. In four of the five studies comparing BMT and IFN-alpha, median survival had not yet been reached in the BMT groups in 6--10 years. Median survival in the IFN-alpha arms ranged from 5.2 to 7 years. The BMT group gained a survival advantage over IFN-alpha at 3--5.5 years. In the BMT group death due to transplant-related complications ranged from 36 to 45%. The incremental cost-effectiveness ratio (ICER) of imatinib compared with IFN-alpha from the independent model was GBP26,180 per quality-adjusted-life-years (QALY) gained and was relatively robust. Imatinib was less cost-effective than hydroxyurea with an ICER of GBP86,934. CONCLUSIONS: Imatinib appears to be more effective than current standard drug treatments in terms of cytogenetic response and progression-free survival, with fewer side-effects. However, there is uncertainty concerning longer term outcomes, the development of resistance to imatinib, the duration of response and the place of imatinib relative to BMT. New issues are continually arising, such as optimal management pathways and combination therapies. Recommendations for research include: long-term follow-up data from the first- and second-line imatinib trials; investigation into specific subgroups, e.g. high-risk patients, the elderly, children or those eligible for BMT; long-term comparisons of imatinib with BMT performed in early stages of CML; the use of imatinib in combination with other therapies, and further detailed economic studies. Investigation of the impact of CML and imatinib on quality of life is also important.

The effectiveness and cost-effectiveness of microwave and thermal balloon endometrial ablation for heavy menstrual bleeding: a systematic review and economic modelling.

OBJECTIVES: To estimate the clinical effectiveness and cost-effectiveness of microwave endometrial ablation (MEA) and thermal balloon endometrial ablation (TBEA) for heavy menstrual bleeding (HMB), compared with the existing (first-generation) endometrial ablation (EA) techniques of transcervical resection (TCRE) and rollerball (RB) ablation, and hysterectomy. DATA SOURCES: Electronic databases, bibliographies of articles, and also experts in the field and relevant industry bodies were asked to provide information. REVIEW METHODS: A detailed search strategy was carried out to identify systematic reviews and controlled trials of MEA and TBEA versus first-generation techniques for EA. In addition to electronic database searching, reference lists were hand-searched and information sought from manufacturers of EA devices and by experts in the field. A deterministic Markov model was developed to assess cost-effectiveness. Data for the model were taken from a range of sources. RESULTS: The systematic review of first-generation EA techniques versus hysterectomy found that EA offered an alternative to hysterectomy for HMB, with fewer complications and a shorter recovery period. Satisfaction and effectiveness were high for both MEA and TBEA. Costs were lower with EA although the difference narrows over time. Second-generation EA techniques are an alternative treatment to first-generation techniques for HMB, and first-generation techniques are known to offer an alternative to hysterectomy. Although no trials of second-generation techniques and hysterectomy have been undertaken, it seems reasonable to assume that second-generation techniques also offer an alternative surgical treatment. Using the model to assess cost-effectiveness, costs were very slightly higher for MEA when compared to TBEA, and differences in quality-adjusted life-years (QALYs) were negligible. For MEA compared with transcervical resection of the endometrium (TCRE) and RB ablation, costs were slightly lower with MEA and MEA accrued very slightly more QALYs. Compared with hysterectomy, MEA costs less and accrues slightly fewer QALYs. For TBEA compared with TCRE and RB ablation, costs were lower with TBEA and TBEA accrued slightly more QALYs. Compared with hysterectomy, TBEA costs moderately less and accrues moderately fewer QALYs. CONCLUSIONS: Overall, there were few significant differences between the outcomes of first- and second-generation techniques including bleeding, satisfaction and QoL measures and repeat surgery rates. Second-generation techniques had significantly shorter operating and theatre times and there appear to be fewer serious perioperative adverse effects with second-generation techniques and postoperative effects are similar. Compared with hysterectomy, TCRE and RB are quicker to perform and result in shorter hospitalisation and faster return to work. Hysterectomy results in more adverse effects and is more expensive, although the need for retreatment leads this difference to decrease over time. Satisfaction with hysterectomy is initially higher, but there is no significant difference after 2 years. The economic model suggests that second-generation techniques are more cost-effective than first-generation techniques of EA for HMB. Both TBEA and MEA appear to be less costly than hysterectomy, although the latter results in more QALYs. Further research is suggested to make direct comparisons of the cost-effectiveness of second-generation EA techniques, to carry out longer term follow-up for all methods of EA in RCTs, and to develop more sophisticated modelling studies. Further research is also recommended into HMB to establish health-state utility values, its surgical treatment, convalescence, complications of treatment, symptoms and patient satisfaction.