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Background: Alzheimer’s disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK. Objectives: Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009). Data sources: Electronic databases were searched for systematic reviews and/or meta-analyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases – Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases – NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects. Review methods: The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE). Interventions: mild AD (MMSE 21–26) – donepezil, galantamine and rivastigmine; moderate AD (MMSE 10–20) – donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of £30,000 per QALY (27% at a WTP of £20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£69,592 vs £69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £30,000 per QALY is 38% (and 28% at a WTP of £20,000 per QALY). The deterministic ICER for memantine is £32,100 per/QALY and the probabilistic ICER is £36,700 per/QALY. Limitations: Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters. Conclusions: The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug’s use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. Research priorities: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis. Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Chronic myeloid leukaemia (CML) is a form of cancer affecting the blood, characterised by excessive proliferation of white blood cells in the bone marrow and circulating blood. In the UK, an estimated 560 new cases of CML are diagnosed each year. Objectives: The purpose of this study was to assess the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in the treatment of people with imatinib-resistant (ImR) and imatinib-intolerant (ImI) CML. A systematic review of the clinical effectiveness literature, a review of manufacturer submissions and a critique and exploration of manufacturer submissions for accelerated phase and blast crisis CML were carried out and a decision-analytic model was developed to estimate the cost-effectiveness of dasatinib and nilotinib in chronic phase CML. Systematic review methods: Key databases were searched for relevant studies from their inception to June 2009 [MEDLINE (including MEDLINE In-Process & Other Non-Indexed Citations), EMBASE, (ISI Web of Science) Conference Proceedings Citation Index and four others]. One reviewer assessed titles and abstracts of studies identified by the search strategy, with a sample checked by a second reviewer. The full text of relevant papers was obtained and screened against the full inclusion criteria independently by two reviewers. Data from included studies were extracted by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through narrative review. Economic evaluation methods: Cost-effectiveness analyses reported in manufacturer submissions to the National Institute of Health and Clinical Excellence were critically appraised and summarised narratively. In addition, the models for accelerated phase and blast crisis underwent a more detailed critique and exploration. Two separate decision-analytic models were developed for chronic phase CML, one simulating a cohort of individuals who have shown or developed resistance to normal dose imatinib and one representing individuals who have been unable to continue imatinib treatment owing to adverse events. One-way, multiway and probabilistic sensitivity analyses were performed to explore structural and parameter uncertainty. Results: Fifteen studies were included in the systematic review. Chronic phase: effectiveness data were limited but dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic response and haematological response in both ImR and ImI populations. In terms of cost-effectiveness, it was extremely difficult to reach any conclusions regarding either agent in the ImR population. All three models (Novartis, PenTAG and Bristol-Myers Squibb) were seriously flawed in one way or another, as a consequence of the paucity of data appropriate to construct robust decision-analytic models. Accelerated and blast crisis: all available data originated from observational single-arm studies and there were considerable and potentially important differences in baseline characteristics which seriously undermined any process for making meaningful comparisons between treatments. Owing to a lack of available clinical data, de novo models of accelerated phase and blast crisis have not been developed. The economic evaluations carried out by the manufacturers of nilotinib and dasatinib were seriously undermined by the absence of evidence on high-dose imatinib in these populations. Limitations: The study has been necessarily constrained by the paucity of available clinical data, the differences in definitions used in the studies and the subsequent impossibility of undertaking a meaningful cost-effectiveness analyses to inform all policy questions. Conclusions: Dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic and haematological responses in both ImR and ImI populations. It was difficult to reach any cost-effectiveness conclusions as a consequence of the paucity of the data. Future research should include a three-way, double-blind, randomised clinical trial of dasatinib, nilotinib and high-dose imatinib. Funding: The National Institute of Health Research Healthy Technology Assessment Programme.

Background: Exercise referral schemes (ERS) aim to identify inactive adults in the primary-care setting. The GP or health-care professional then refers the patient to a third-party service, with this service taking responsibility for prescribing and monitoring an exercise programme tailored to the needs of the individual. Objective: To assess the clinical effectiveness and cost-effectiveness of ERS for people with a diagnosed medical condition known to benefit from physical activity (PA). The scope of this report was broadened to consider individuals without a diagnosed condition who are sedentary. Data sources: MEDLINE; EMBASE; PsycINFO; The Cochrane Library, ISI Web of Science; SPORTDiscus and ongoing trial registries were searched (from 1990 to October 2009) and included study references were checked. Methods: Systematic reviews: the effectiveness of ERS, predictors of ERS uptake and adherence, and the cost-effectiveness of ERS; and the development of a decision-analytic economic model to assess cost-effectiveness of ERS. Results: Seven randomised controlled trials (UK, n = 5; non-UK, n = 2) met the effectiveness inclusion criteria, five comparing ERS with usual care, two compared ERS with an alternative PA intervention, and one to an ERS plus a self-determination theory (SDT) intervention. In intention-to-treat analysis, compared with usual care, there was weak evidence of an increase in the number of ERS participants who achieved a self-reported 90–150 minutes of at least moderate-intensity PA per week at 6–12 months’ follow-up [pooled relative risk (RR) 1.11, 95% confidence interval 0.99 to 1.25]. There was no consistent evidence of a difference between ERS and usual care in the duration of moderate/vigorous intensity and total PA or other outcomes, for example physical fitness, serum lipids, health-related quality of life (HRQoL). There was no between-group difference in outcomes between ERS and alternative PA interventions or ERS plus a SDT intervention. None of the included trials separately reported outcomes in individuals with medical diagnoses. Fourteen observational studies and five randomised controlled trials provided a numerical assessment of ERS uptake and adherence (UK, n = 16; non-UK, n = 3). Women and older people were more likely to take up ERS but women, when compared with men, were less likely to adhere. The four previous economic evaluations identified suggest ERS to be a cost-effective intervention. Indicative incremental cost per quality-adjusted life-year (QALY) estimates for ERS for various scenarios were based on a de novo model-based economic evaluation. Compared with usual care, the mean incremental cost for ERS was £169 and the mean incremental QALY was 0.008, with the base-case incremental cost-effectiveness ratio at £20,876 per QALY in sedentary people without a medical condition and a cost per QALY of £14,618 in sedentary obese individuals, £12,834 in sedentary hypertensive patients, and £8414 for sedentary individuals with depression. Estimates of cost-effectiveness were highly sensitive to plausible variations in the RR for change in PA and cost of ERS. Limitations: We found very limited evidence of the effectiveness of ERS. The estimates of the cost-effectiveness of ERS are based on a simple analytical framework. The economic evaluation reports small differences in costs and effects, and findings highlight the wide range of uncertainty associated with the estimates of effectiveness and the impact of effectiveness on HRQoL. No data were identified as part of the effectiveness review to allow for adjustment of the effect of ERS in different populations. Conclusions: There remains considerable uncertainty as to the effectiveness of ERS for increasing activity, fitness or health indicators or whether they are an efficient use of resources in sedentary people without a medical diagnosis. We failed to identify any trial-based evidence of the effectiveness of ERS in those with a medical diagnosis.: Future work should include randomised controlled trials assessing the cinical effectiveness and cost-effectivenesss of ERS in disease groups that may benefit from PA. Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Order communication systems (OCS) are computer applications used to enter diagnostic and therapeutic patient care orders and to view test results. Many potential benefits of OCS have been identified including improvements in clinician ordering patterns, optimisation of clinical time, and aiding communication processes between clinicians and different departments. Many OCS now include computerised decision support systems (CDSS), which are information systems designed to improve clinical decision-making. CDSS match individual patient characteristics to a computerised knowledge base, and software algorithms generate patient-specific recommendations. Objectives: To investigate which CDSS in OCS are in use within the UK and the impact of CDSS in OCS for diagnostic, screening or monitoring test ordering compared to OCS without CDSS. To determine what features of CDSS are associated with clinician or patient acceptance of CDSS in OCS and what is known about the cost-effectiveness of CDSS in diagnostic, screening or monitoring test OCS compared to OCS without CDSS. Data sources: A generic search to identify potentially relevant studies for inclusion was conducted using MEDLINE, EMBASE, Cochrane Controlled Trials Register (CCTR), CINAHL (Cumulative Index to Nursing and Allied Health Literature), DARE (Database of Abstracts of Reviews of Effects), Health Technology Assessment (HTA) database, IEEE (Institute of Electrical and Electronic Engineers) Xplore digital library, NHS Economic Evaluation Database (NHS EED) and EconLit, searched between 1974 and 2009 with a total of 22,109 titles and abstracts screened for inclusion. Review methods: CDSS for diagnostic, screening and monitoring test ordering OCS in use in the UK were identified through contact with the 24 manufacturers/suppliers currently contracted by the National Project for Information Technology (NpfIT) to provide either national or specialist decision support. A generic search to identify potentially relevant studies for inclusion in the review was conducted on a range of medical, social science and economic databases. The review was undertaken using standard systematic review methods, with studies being screened for inclusion, data extracted and quality assessed by two reviewers. Results were broadly grouped according to the type of CDSS intervention and study design where possible. These were then combined using a narrative synthesis with relevant quantitative results tabulated. Results: Results of the studies included in review were highly mixed and equivocal, often both within and between studies, but broadly showed a beneficial impact of the use of CDSS in conjunction with OCS over and above OCS alone. Overall, if the findings of both primary and secondary outcomes are taken into account, then CDSS significantly improved practitioner performance in 15 out of 24 studies (62.5%). Only two studies covered the cost-effectiveness of CDSS: a Dutch study reported a mean cost decrease of 3% for blood tests orders (€ 639) in each of the intervention clinics compared with a 2% (€ 208) increase in control clinics in test costs; and a Spanish study reported a significant increase in the cost of laboratory tests from € 41.8 per patient per annum to € 47.2 after implementation of the system. Limitations: The response rate from the survey of manufacturers and suppliers was extremely low at only 17% and much of the feedback was classified as being commercial-in-confidence (CIC). No studies were identified which assessed the features of CDSS that are associated with clinician or patient acceptance of CDSS in OCS in the test ordering process and only limited data was available on the cost-effectiveness of CDSS plus OCS compared with OCS alone and the findings highly specific. Although CDSS appears to have a potentially small positive impact on diagnostic, screening or monitoring test ordering, the majority of studies come from a limited number of institutions in the USA. Conclusions: If the findings of both primary and secondary outcomes are taken into account then CDSS showed a statistically significant benefit on either process or practitioner performance outcomes in nearly two-thirds of the studies. Furthermore, in four studies that assessed adverse effects of either test cancellation or delay, no significant detrimental effects in terms of additional utilisation of health-care resources or adverse events were observed. We believe the key current need is for a well designed and comprehensive survey, and on the basis of the results of this potentially for evaluation studies in the form of cluster randomised controlled trials or randomised controlled trials which incorporate process, and patient outcomes, as well as full economic evaluations alongside the trials to assess the impact of CDSS in conjunction with OCS versus OCS alone for diagnostic, screening or monitoring test ordering in the NHS. The economic evaluation should incorporate the full costs of potentially developing, testing, and installing the system, including staff training costs. Study registration: Study registration 61.

Objectives: To assess the clinical effectiveness and cost-effectiveness of bevacizumab, combined with interferon (IFN), sorafenib tosylate, sunitinib and temsirolimus in the treatment of people with advanced and/or metastatic renal cell carcinoma (RCC). Data sources: Electronic databases, including MEDLINE, EMBASE and the Cochrane Library, were searched up to September/October 2007 (and again in February 2008). Review methods: Systematic reviews and randomised clinical trials comparing any of the interventions with any of the comparators in participants with advanced and/or metastatic RCC were included, also phase II studies and conference abstracts if there was sufficient detail to adequately assess quality. Results were synthesised narratively and a decision-analytic Markov-type model was developed to simulate disease progression and estimate the cost-effectiveness of the interventions under consideration. Results: A total of 888 titles and abstracts were retrieved in the clinical effectiveness review, including reports of eight clinical trials. Treatment with bevacizumab plus IFN or sunitinib had clinically relevant and statistically significant advantages over treatment with IFN alone, in terms of progression-free survival and tumour response, doubling median progression-free survival from approximately 5 months to 10 months. Temsirolimus had similar advantages over treatment with IFN in terms of progression-free and overall survival, increasing median overall survival from 7.3 to 10.9 months [hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58 to 0.92)], as did sorafenib in comparison with best supportive care in terms of overall survival, progression-free survival and tumour response, with a doubling of progression-free survival (HR 0.51; 95% CI 0.43 to 0.60). However, the last was associated with an increased frequency of hypertension and hand–foot skin reaction compared with placebo. No fully published economic evaluations of any of the interventions could be located. However, estimates from the PenTAG model suggested that none of the interventions would be considered cost-effective at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year (QALY). Estimates of cost per QALY ranged from £71,462 for sunitinib to £171,301 for bevacizumab plus IFN. Although there are many similarities in the methodology and structural assumptions employed by PenTAG and the manufacturers of the interventions, in all cases the cost-effectiveness estimates from the PenTAG model were higher than those presented in the manufacturers’ submissions. Cost-effectiveness estimates were particularly sensitive to variations in the estimates of treatment effectiveness, drug pricing (including dose intensity data), and health-state utility input parameters. Conclusions: Treatment with bevacizumab plus IFN and sunitinib has clinically relevant and statistically significant advantages over treatment with IFN alone in patients with metastatic RCC. In people with three of six risk factors for poor prognosis, temsirolimus had clinically relevant advantages over treatment with IFN, and sorafenib tosylate was superior to best supportive care as second-line therapy. The frequency of adverse events associated with bevacizumab plus IFN, sunitinib and temsirolimus was comparable with that seen with IFN, although the adverse event profile is different. Treatment with sorafenib was associated with a significantly increased frequency of hypertension and hand–foot syndrome. Estimates from the PenTAG model suggested that none of the interventions would be considered cost-effective at a willingness-to-pay threshold of £30,000 per QALY.

Objective: To review the evidence for the effectiveness and cost-effectiveness of storing kidneys from deceased donors prior to transplantation, using cold static storage solutions or pulsatile hypothermic machine perfusion. Data sources: Electronic databases were searched in January 2008 and updated in May 2008 for systematic reviews and/or meta-analyses, randomised controlled trials (RCTs), other study designs and ongoing research. Sources included: Cochrane Library, MEDLINE, EMBASE, CINAHL, ISI Web of Knowledge, DARE, NRR, ReFeR, Current Controlled Trials, and (NHS) HTA. Bibliographies of articles were searched for further relevant studies, and the Food and Drugs Administration (FDA) and European Regulatory Agency Medical Device Safety Service websites were searched. Only English language papers were sought. Review methods: The perfusion machines identified were the LifePort Kidney Transporter® (Organ Recovery Systems) and the RM3 Renal Preservation System® (Waters Medical Systems). The cold storage solutions reviewed were: University of Wisconsin, ViaSpan™; Marshall’s hypertonic citrate, Soltran™; and Genzyme, Celsior™. Each intervention was compared with the others as data permitted. The population was recipients of kidneys from deceased donors. The main outcomes were measures of graft survival, patient survival, delayed graft function (DGF), primary non-function (PNF), discard rates of non-viable kidneys, health-related quality of life and cost-effectiveness. Where data permitted the results of studies were pooled using meta-analysis. A Markov (state transition) model was developed to simulate the main post-transplantation outcomes of kidney graft recipients. Results: Eleven studies were included: three full journal published RCTs, two ongoing RCTs [European Machine Preservation Trial (MPT) and UK Pulsatile Perfusion in Asystolic donor Renal Transplantation (PPART) study], one cohort study, three full journal published retrospective record reviews and two retrospective record reviews published as posters or abstracts only. For LifePort versus ViaSpan, no significant differences were found for DGF, PNF, acute rejection, duration of DGF, creatinine clearance or toxicity, patient survival or graft survival at 6 months, but graft survival was better at 12 months post transplant with machine perfusion (LifePort = 98%, ViaSpan = 94%, p

Visible light optical elements such as lenses and mirrors have counterparts for X-rays. In the visible regime, a variable focusing power can be achieved by an Alvarez lens which consists of a pair of inline planar refractors with a cubic thickness profile. When the two refractors are laterally displaced in opposite directions, the parabolic component of the wavefront is changed resulting in a longitudinal displacement of the focus. This paper reports an implementation of this concept for X-rays using two planar microfabricated refractive elements. The Alvarez X-ray lens can vary the focal distance of an elliptical X-ray mirror or a planar compound X-ray lens over several millimetres. The study presents the first demonstration of an Alvarez X-ray lens which adaptively corrects defocus and astigmatism aberrations of X-ray optics. In addition, the Alvarez X-ray lens eliminates coma aberration in an elliptical mirror, to the lowest order, when combining the lens with an adjustment of the pitch angle of the mirror., (© 2023. Crown.)

A refractive phase corrector optics is proposed for the compensation of fabrication error of X-ray optical elements. Here, at-wavelength wavefront measurements of the focused X-ray beam by knife-edge imaging technique, the design of a three-dimensional corrector plate, its fabrication by 3D printing, and use of a corrector to compensate for X-ray lens figure errors are presented. A rotationally invariant corrector was manufactured in the polymer IP-S TM using additive manufacturing based on the two-photon polymerization technique. The fabricated corrector was characterized at the B16 Test beamline, Diamond Light Source, UK, showing a reduction in r.m.s. wavefront error of a Be compound refractive Lens (CRL) by a factor of six. The r.m.s. wavefront error is a figure of merit for the wavefront quality but, for X-ray lenses, with significant X-ray absorption, a form of the r.m.s. error with weighting proportional to the transmitted X-ray intensity has been proposed. The knife-edge imaging wavefront-sensing technique was adapted to measure rotationally variant wavefront errors from two different sets of Be CRL consisting of 98 and 24 lenses. The optical aberrations were then quantified using a Zernike polynomial expansion of the 2D wavefront error. The compensation by a rotationally invariant corrector plate was partial as the Be CRL wavefront error distribution was found to vary with polar angle indicating the presence of non-spherical aberration terms. A wavefront correction plate with rotationally anisotropic thickness is proposed to compensate for anisotropy in order to achieve good focusing by CRLs at beamlines operating at diffraction-limited storage rings., (open access.)

In the past years, a significant amount of effort has been directed at the observation and characterisation of caries using experimental techniques. Nevertheless, relatively little progress has been made in numerical modelling of the underlying demineralisation process. The present study is the first attempt to provide a simplified calculation framework for the numerical simulation of the demineralisation process at the length scale of enamel rods and its validation by comparing the data with statistical analysis of experimental results. FEM model was employed to simulate a time-dependent reaction-diffusion equation process in which H ions diffuse and cause demineralisation of the enamel. The local orientation of the hydroxyapatite crystals was taken into account. Experimental analysis of the demineralising front was performed using advanced high-resolution synchrotron X-ray micro-Computed Tomography. Further experimental investigations were conducted by means of SEM and STEM imaging techniques. Besides establishing and validating the new modelling framework, insights into the role of the etchant solution pH level were obtained. Additionally, some light was shed on the origin of different types of etching patterns by simulating the demineralisation process at different etching angles of attack. The implications of this study pave the way for simulations of enamel demineralisation within different complex scenarios and across the range of length scales. Indeed, the framework proposed can incorporate the presence of chemical species other than H ions and their diffusion and reaction leading to dissolution and re-precipitation of hydroxyapatite. It is the authors' hope and aspiration that ultimately this work will help identify new ways of controlling and preventing caries., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors. Published by Elsevier B.V. on behalf of Cairo University.)

Nylon-12 is an important structural polymer in wide use in the form of fibres and bulk structures. Fused filament fabrication (FFF) is an extrusion-based additive manufacturing (AM) method for rapid prototyping and final product manufacturing of thermoplastic polymer objects. The resultant microstructure of FFF-produced samples is strongly affected by the cooling rates and thermal gradients experienced across the part. The crystallisation behaviour during cooling and solidification influences the micro- and nano-structure, and deserves detailed investigation. A commercial Nylon-12 filament and FFF-produced Nylon-12 parts were studied by differential scanning calorimetry (DSC) and wide-angle X-ray scattering (WAXS) to examine the effect of cooling rates under non-isothermal crystallisation conditions on the microstructure and properties. Slower cooling rates caused more perfect crystallite formation, as well as alteration to the thermal properties.

We identify the ways the policies of leading international bioethics journals limit the participation of researchers working in the resource-constrained settings of low- and middle-income countries (LMICs) in the development of the field of bioethics. Lack of access to essential scholarly resources makes it extremely difficult, if not impossible, for many LMIC bioethicists to learn from, meaningfully engage in, and further contribute to the global bioethics discourse. Underrepresentation of LMIC perspectives in leading journals sustains the hegemony of Western bioethics, limits the presentation of diverse moral visions of life, health, and medicine, and undermines aspirations to create a truly "global" bioethics. Limited attention to this problem indicates a lack of empathy and moral imagination on the part of bioethicists in high-income countries, raises questions about the ethics of bioethics, and highlights the urgent need to find ways to remedy this social injustice.

Background: Evidence from systematic reviews of observational studies suggest that hormone replacement therapy (HT) may have beneficial effects in reducing the incidence of cardiovascular disease (CVD) events in post-menopausal women. This is an updated version of a Cochrane review first published in 2005 (Gabriel-Sanchez 2005)., Objectives: To assess the effects of HT for the prevention of CVD in post-menopausal women, and whether there are differential effects between use of single therapy alone compared to combination HT and use in primary or secondary prevention., Search Methods: We searched the following databases to April 2010: Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE and LILACS., Selection Criteria: Randomised controlled trials (RCTs) of women comparing orally administered HT with placebo with a minimum of six-months follow-up., Data Collection and Analysis: Two authors independently assessed study quality and extracted data. Risk Ratios (RR) with 95% confidence intervals were calculated for each outcome. Results were combined using fixed-effect meta-analyses, and where possible, further stratified analyses conducted to assess the effect of time on treatment. Additionally, univariate meta-regression analyses were undertaken to assess whether length of trial follow-up, single or combination treatment, or whether treatment for primary or secondary prevention were potential predictors for a number of CVD outcomes in the trials., Main Results: Four new trials were identified through the update; one trial included in the previous review was excluded. Therefore the review included 13 trials with a total of 38,171 post-menopausal women. Overall, single and combination HT in both primary and secondary prevention conferred no protective effects for all cause mortality, CVD death, non-fatal MI, or angina. There were no significant differences in the number of coronary artery by-pass procedures or angioplasties performed between the trial arms. However there was an increased risk of stroke for both primary and secondary prevention when combination and single HT was combined, RR 1.26 (95% CI 1.11 to 1.43), in venous thromboembolic events, RR 1.89 (95% CI 1.58 to 2.26) and in pulmonary embolism RR 1.84 (95% CI 1.42 to 2.37) relative to placebo. The associated numbers needed-to-harm (NNH) were 164, 109 and 243 for stroke, venous thromboembolism and pulmonary embolism respectively., Authors' Conclusions: Treatment with HT in post-menopausal women for either primary or secondary prevention of CVD events is not effective, and causes an increase in the risk of stroke, and venous thromboembolic events. HT should therefore only be considered for women seeking relief from menopausal symptoms. Short-term HT treatment should be at the lowest effective dose, and used with caution in women with predisposing risk factors for CVD events.

Introduction: in 2007 the National Institute of Health and Clinical Excellence (NICE) restricted the use of acetylcholinesterase inhibitors and memantine., Methods: we conducted a health technology assessment (HTA) of the effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of AD to re-consider and up-date the evidence base used to inform the 2007 NICE decision. The systematic review of effectiveness targeted randomised controlled trials. A comprehensive search, including MEDLINE, Embase and the Cochrane Library, was conducted from January 2004 to March 2010. All key review steps were done by two reviewers. Random effects meta-analysis was conducted. The cost-effectiveness was assessed using a cohort-based model with three health states: pre-institutionalised, institutionalised and dead. The perspective was NHS and Personal Social Services and the cost year 2009., Results: confidence about the size and statistical significance of the estimates of effect of galantamine, rivastigmine and memantine improved on function and global impact in particular. Cost-effectiveness also changed. For donepezil, galantamine and rivastigmine, the incremental cost per quality-adjusted life year (QALY) in 2004 was above £50,000; in 2010 the same drugs 'dominated' best supportive care (improved clinical outcome at reduced cost). This was primarily because of changes in the modelled costs of introducing the drugs. For memantine, the cost-effectiveness also improved from a range of £37-53,000 per QALY gained to a base-case of £32,000., Conclusion: there has been a change in the evidence base between 2004 and 2010 consistent with the change in NICE guidance. Further evolution in cost-effectiveness estimates is possible particularly if there are changes in drug prices.

Background: The effectiveness of exercise referral schemes (ERS) is influenced by uptake and adherence to the scheme. The identification of factors influencing low uptake and adherence could lead to the refinement of schemes to optimise investment., Objectives: To quantify the levels of ERS uptake and adherence and to identify factors predictive of uptake and adherence., Methods: A systematic review and meta-analysis was undertaken. MEDLINE, EMBASE, PsycINFO, Cochrane Library, ISI WOS, SPORTDiscus and ongoing trial registries were searched (to October 2009) and included study references were checked. Included studies were required to report at least one of the following: (1) a numerical measure of ERS uptake or adherence and (2) an estimate of the statistical association between participant demographic or psychosocial factors (eg, level of motivation, self-efficacy) or programme factors and uptake or adherence to ERS., Results: Twenty studies met the inclusion criteria, six randomised controlled trials (RCTs) and 14 observational studies. The pooled level of uptake in ERS was 66% (95% CI 57% to 75%) across the observational studies and 81% (95% CI 68% to 94%) across the RCTs. The pooled level of ERS adherence was 49% (95% CI 40% to 59%) across the observational studies and 43% (95% CI 32% to 54%) across the RCTs. Few studies considered anything other than gender and age. Women were more likely to begin an ERS but were less likely to adhere to it than men. Older people were more likely to begin and adhere to an ERS., Limitations: Substantial heterogeneity was evident across the ERS studies. Without standardised definitions, the heterogeneity may have been reflective of differences in methods of defining uptake and adherence across studies., Conclusions: To enhance our understanding of the variation in uptake and adherence across ERS and how these variations might affect physical activity outcomes, future trials need to use quantitative and qualitative methods.

Introduction: Unintentional injuries to children in the outdoors have a significant impact on child mortality, development and healthcare costs. This paper presents the findings of a systematic review about the effectiveness of programs that provided information, advice or education about the prevention of unintentional injuries to children under 15 years during outdoor play and leisure., Methods: A structured search strategy was conducted in a range of databases. All report titles and abstracts were screened using pre-defined criteria. Included reports were quality appraised using a modified Graphical Appraisal Tool for Epidemiological studies (GATE) tool. All quality appraisals and data extraction were checked by a second reviewer. If not provided in the original reports, ORs and mean differences were calculated, where sufficient data were available., Results: Twenty-three studies met the inclusion criteria. There was a paucity of robust study designs. The majority of studies only reported a short-term follow-up of intermediate outcome measures. Only two studies measured injury rates; both reported a reduction, but both studies also had considerable methodological weaknesses. The five studies that measured the use of protective equipment reported mixed results, although there is some evidence that suggests that more extensive educational programs (such as health fairs and media campaigns) increase their use. The 20 studies that measured behaviour, attitude or knowledge outcomes reported highly mixed results., Discussion: Methodological weaknesses of the included studies limit support for a particular course of action. To better inform policy and practice, future research should (1) use robust study designs and (2) not rely on short-term proxy outcome measures.

Background: Chronic myeloid leukaemia (CML) is a form of cancer affecting the blood, characterised by excessive proliferation of white blood cells in the bone marrow and circulating blood. In the UK, an estimated 560 new cases of CML are diagnosed each year., Objectives: The purpose of this study was to assess the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in the treatment of people with imatinib-resistant (ImR) and imatinib-intolerant (ImI) CML. A systematic review of the clinical effectiveness literature, a review of manufacturer submissions and a critique and exploration of manufacturer submissions for accelerated phase and blast crisis CML were carried out and a decision-analytic model was developed to estimate the cost-effectiveness of dasatinib and nilotinib in chronic phase CML. SYSTEMATIC REVIEW METHODS: Key databases were searched for relevant studies from their inception to June 2009 [MEDLINE (including MEDLINE In-Process & Other Non-Indexed Citations), EMBASE, (ISI Web of Science) Conference Proceedings Citation Index and four others]. One reviewer assessed titles and abstracts of studies identified by the search strategy, with a sample checked by a second reviewer. The full text of relevant papers was obtained and screened against the full inclusion criteria independently by two reviewers. Data from included studies were extracted by one reviewer and checked by a second. Clinical effectiveness studies were synthesised through narrative review. ECONOMIC EVALUATION METHODS: Cost-effectiveness analyses reported in manufacturer submissions to the National Institute of Health and Clinical Excellence were critically appraised and summarised narratively. In addition, the models for accelerated phase and blast crisis underwent a more detailed critique and exploration. Two separate decision-analytic models were developed for chronic phase CML, one simulating a cohort of individuals who have shown or developed resistance to normal dose imatinib and one representing individuals who have been unable to continue imatinib treatment owing to adverse events. One-way, multiway and probabilistic sensitivity analyses were performed to explore structural and parameter uncertainty., Results: Fifteen studies were included in the systematic review. Chronic phase: effectiveness data were limited but dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic response and haematological response in both ImR and ImI populations. In terms of cost-effectiveness, it was extremely difficult to reach any conclusions regarding either agent in the ImR population. All three models (Novartis, PenTAG and Bristol-Myers Squibb) were seriously flawed in one way or another, as a consequence of the paucity of data appropriate to construct robust decision-analytic models. Accelerated and blast crisis: all available data originated from observational single-arm studies and there were considerable and potentially important differences in baseline characteristics which seriously undermined any process for making meaningful comparisons between treatments. Owing to a lack of available clinical data, de novo models of accelerated phase and blast crisis have not been developed. The economic evaluations carried out by the manufacturers of nilotinib and dasatinib were seriously undermined by the absence of evidence on high-dose imatinib in these populations., Limitations: The study has been necessarily constrained by the paucity of available clinical data, the differences in definitions used in the studies and the subsequent impossibility of undertaking a meaningful cost-effectiveness analyses to inform all policy questions., Conclusions: Dasatinib and nilotinib appeared efficacious in terms of obtaining cytogenetic and haematological responses in both ImR and ImI populations. It was difficult to reach any cost-effectiveness conclusions as a consequence of the paucity of the data. Future research should include a three-way, double-blind, randomised clinical trial of dasatinib, nilotinib and high-dose imatinib.

Background: Alzheimer’s disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK., Objectives: Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009)., Data Sources: Electronic databases were searched for systematic reviews and/or metaanalyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases--Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases--NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects., Review Methods: The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE)., Interventions: mild AD (MMSE 21-26)--donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10)--memantine. Comparators: mild AD (MMSE 21-26)--placebo or best supportive care (BSC); moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10)--placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of life, adverse events, costs and cost-effectiveness. Where appropriate, data were pooled using pair-wise meta-analysis, multiple outcome measures, metaregression and mixedtreatment comparisons. The decision model was based broadly on the structure of the three-state Markov model described in the previous technology assessment report, based upon time to institutionalisation, parameterised with updated estimates of effectiveness, costs and utilities., Results: Notwithstanding the uncertainty of our results, we found in the base case that the AChEIs are probably cost saving at a willingness-to-pay (WTP) of £’30,000 per qualityadjusted life-year (QALY) for people with mild-to-moderate AD. For this class of drugs, there is a > 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of £’30,000 per QALY (27% at a WTP of £’20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£’69,592 vs £’69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £’30,000 per QALY is 38% (and 28% at a WTP of £’20,000 per QALY). The deterministic ICER for memantine is £’32,100 per/QALY and the probabilistic ICER is £’36,700 per/QALY., Limitations: Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters., Conclusions: The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug’s use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. RESEARCH PRIORITIES: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis., Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Exercise referral schemes (ERS) aim to identify inactive adults in the primary-care setting. The GP or health-care professional then refers the patient to a third-party service, with this service taking responsibility for prescribing and monitoring an exercise programme tailored to the needs of the individual., Objective: To assess the clinical effectiveness and cost-effectiveness of ERS for people with a diagnosed medical condition known to benefit from physical activity (PA). The scope of this report was broadened to consider individuals without a diagnosed condition who are sedentary., Data Sources: MEDLINE; EMBASE; PsycINFO; The Cochrane Library, ISI Web of Science; SPORTDiscus and ongoing trial registries were searched (from 1990 to October 2009) and included study references were checked., Methods: Systematic reviews: the effectiveness of ERS, predictors of ERS uptake and adherence, and the cost-effectiveness of ERS; and the development of a decision-analytic economic model to assess cost-effectiveness of ERS., Results: Seven randomised controlled trials (UK, n = 5; non-UK, n = 2) met the effectiveness inclusion criteria, five comparing ERS with usual care, two compared ERS with an alternative PA intervention, and one to an ERS plus a self-determination theory (SDT) intervention. In intention-to-treat analysis, compared with usual care, there was weak evidence of an increase in the number of ERS participants who achieved a self-reported 90-150 minutes of at least moderate-intensity PA per week at 6-12 months' follow-up [pooled relative risk (RR) 1.11, 95% confidence interval 0.99 to 1.25]. There was no consistent evidence of a difference between ERS and usual care in the duration of moderate/vigorous intensity and total PA or other outcomes, for example physical fitness, serum lipids, health-related quality of life (HRQoL). There was no between-group difference in outcomes between ERS and alternative PA interventions or ERS plus a SDT intervention. None of the included trials separately reported outcomes in individuals with medical diagnoses. Fourteen observational studies and five randomised controlled trials provided a numerical assessment of ERS uptake and adherence (UK, n = 16; non-UK, n = 3). Women and older people were more likely to take up ERS but women, when compared with men, were less likely to adhere. The four previous economic evaluations identified suggest ERS to be a cost-effective intervention. Indicative incremental cost per quality-adjusted life-year (QALY) estimates for ERS for various scenarios were based on a de novo model-based economic evaluation. Compared with usual care, the mean incremental cost for ERS was £169 and the mean incremental QALY was 0.008, with the base-case incremental cost-effectiveness ratio at £20,876 per QALY in sedentary people without a medical condition and a cost per QALY of £14,618 in sedentary obese individuals, £12,834 in sedentary hypertensive patients, and £8414 for sedentary individuals with depression. Estimates of cost-effectiveness were highly sensitive to plausible variations in the RR for change in PA and cost of ERS., Limitations: We found very limited evidence of the effectiveness of ERS. The estimates of the cost-effectiveness of ERS are based on a simple analytical framework. The economic evaluation reports small differences in costs and effects, and findings highlight the wide range of uncertainty associated with the estimates of effectiveness and the impact of effectiveness on HRQoL. No data were identified as part of the effectiveness review to allow for adjustment of the effect of ERS in different populations., Conclusions: There remains considerable uncertainty as to the effectiveness of ERS for increasing activity, fitness or health indicators or whether they are an efficient use of resources in sedentary people without a medical diagnosis. We failed to identify any trial-based evidence of the effectiveness of ERS in those with a medical diagnosis. Future work should include randomised controlled trials assessing the cinical effectiveness and cost-effectivenesss of ERS in disease groups that may benefit from PA., Funding: The National Institute for Health Research Health Technology Assessment programme.

Objectives: To estimate the cost-effectiveness of dasatinib and nilotinib compared with high-dose imatinib for people with chronic phase chronic myeloid leukemia, which are resistant to normal-dose imatinib and compared with interferon-α for people intolerant to imatinib, from the perspective of the UK National Health Service., Methods: An an area under the curve partitioned survival model was developed to estimate the cost-effectiveness of dasatinib and nilotinib. Clinical effectiveness evidence was taken mostly from single-arm trials., Results: Both progression-free survival and overall survival are highly uncertain. In the base case, patients take nilotinib for much less time than dasatinib. Nilotinib is expected to dominate high-dose imatinib, yielding slightly more (0.32) quality-adjusted life years (QALYs) at slightly less cost (£11,100 [pound sterling]) per person. Dasatinib is predicted to provide slightly more (0.53) QALYs at substantially greater cost (£48,900), yielding a very high incremental cost-effectiveness ratio of £91,500 QALY against high-dose imatinib. Cost-effectiveness, however, changes radically under the plausible assumption that the drugs are taken for the same time. For people intolerant to imatinib, nilotinib is expected to yield an incremental cost-effectiveness ratio of £104,700/QALY, and dasatinib £82,600/QALY compared with interferon-α. Further, both drugs represent poor value for money for a range of plausible structural assumptions., Conclusions: The model should be viewed as an exploratory analysis of the cost-effectiveness of dasatinib and nilotinib because it relies on many assumptions. Whilst clinical data remains immature, the cost-effectiveness of dasatinib and nilotinib for imatinib-resistant people is highly uncertain. Both nilotinib and dasatinib are highly unlikely to be cost-effective versus interferon-α for people intolerant to imatinib., (Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Objective: To assess the impact of exercise referral schemes on physical activity and health outcomes. Design Systematic review and meta-analysis., Data Sources: Medline, Embase, PsycINFO, Cochrane Library, ISI Web of Science, SPORTDiscus, and ongoing trial registries up to October 2009. We also checked study references. Study selection Design: randomised controlled trials or non-randomised controlled (cluster or individual) studies published in peer review journals., Population: sedentary individuals with or without medical diagnosis. Exercise referral schemes defined as: clear referrals by primary care professionals to third party service providers to increase physical activity or exercise, physical activity or exercise programmes tailored to individuals, and initial assessment and monitoring throughout programmes. Comparators: usual care, no intervention, or alternative exercise referral schemes., Results: Eight randomised controlled trials met the inclusion criteria, comparing exercise referral schemes with usual care (six trials), alternative physical activity intervention (two), and an exercise referral scheme plus a self determination theory intervention (one). Compared with usual care, follow-up data for exercise referral schemes showed an increased number of participants who achieved 90-150 minutes of physical activity of at least moderate intensity per week (pooled relative risk 1.16, 95% confidence intervals 1.03 to 1.30) and a reduced level of depression (pooled standardised mean difference -0.82, -1.28 to -0.35). Evidence of a between group difference in physical activity of moderate or vigorous intensity or in other health outcomes was inconsistent at follow-up. We did not find any difference in outcomes between exercise referral schemes and the other two comparator groups. None of the included trials separately reported outcomes in individuals with specific medical diagnoses. Substantial heterogeneity in the quality and nature of the exercise referral schemes across studies might have contributed to the inconsistency in outcome findings. Conclusions Considerable uncertainty remains as to the effectiveness of exercise referral schemes for increasing physical activity, fitness, or health indicators, or whether they are an efficient use of resources for sedentary people with or without a medical diagnosis.

In children under the age of five, the majority of unintentional injuries occur in the home, with higher levels of injury morbidity and mortality being found among those from more deprived backgrounds. This paper presents the findings of a systematic review about the effectiveness of programmes in decreasing unintentional injury rates to children (aged up to 15 years) in the home. The effectiveness of the provision of home safety equipment with or without installation, safety education or a home risk assessment is presented by outcome: injury rates, installation of smoke alarms and installation of other home safety equipment. Analysis of the statistically significant evidence suggests that few programmes reduce injury rates in children except where home safety equipment is supplied in conjunction with a home risk assessment, although this effect was only evident in households where a child had previously suffered an unintentional injury. The distribution of smoke alarms alone is insufficient for improving installation rates; programmes containing an education component showed more success. Interventions integrated into wider health programmes, where trusting relationships with householders were cultivated and/or where specific safety issues identified by a community were responded to also showed greater success in increasing smoke alarm installation rates. The evidence of effectiveness on installation rates of other home safety equipment is highly mixed, although there is some evidence to suggest that installation rates always decrease after 6 months. Where stair gates are both supplied and installed, inequalities in rates of use may be reduced.

Electronic database search strategies have developed substantially over the course of the past two decades, but their optimal use within a broader search strategy remains unclear. This article evaluates the use of a range of search strategies to identify qualitative evidence on the implementation of cardiovascular disease (CVD) prevention programs. Within the time-limited context of the production of a policy-relevant systematic review, the authors found the protocol-driven, targeted, and reference-checking search strategies to be the most effective, while obtaining authors' suggestions proved to be a resource-intensive process with negligible results. Weaknesses in the indexing of qualitative research in electronic literature databases mean that the sensitivity of searches may need to be reduced to allow time for other search strategies to be implemented. Expert knowledge may be optimally used through involving experts in the design and implementation of a search strategy, rather than solely as a source of citations.

Background: Psychological symptoms are strongly associated with coronary heart disease (CHD), and many psychological treatments are offered following cardiac events or procedures., Objectives: Update the existing Cochrane review to (1) determine the independent effects of psychological interventions in patients with CHD (principal outcome measures included total or cardiac-related mortality, cardiac morbidity, depression, and anxiety) and (2) explore study-level predictors of the impact of these interventions., Search Strategy: The original review searched Cochrane Controleed Trials Register (CCTR, Issue 4, 2001), MEDLINE, EMBASE, PsycINFO, and CINAHL to December 2001. This was updated by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE, PsycINFO and CINAHL from 2001 to January 2009. In addition, we searched reference lists of papers, and expert advice was sought for the original and update review., Selection Criteria: Randomised controlled trials of psychological interventions compared to usual care, administered by trained staff. Only studies estimating the independent effect of the psychological component with a minimum follow-up of six months. Adults with specific diagnosis of CHD., Data Collection and Analysis: Titles and abstracts of all references screened for eligibility by two reviewers independently; data extracted by the lead author and checked by a second reviewer. Authors contacted where possible to obtain missing information., Main Results: There was no strong evidence that psychological intervention reduced total deaths, risk of revascularisation, or non-fatal infarction. Amongst a smaller group of studies reporting cardiac mortality there was a modest positive effect of psychological intervention (relative risk: 0.80 (95% CI 0.64 to 1.00)). Furthermore, psychological intervention did result in small/moderate improvements in depression, standardised mean difference (SMD): -0.21 (95% CI -0.35, -0.08) and anxiety, SMD: -0.25 (95% CI -0.48 to -0.03). Results for mortality indicated some evidence of small-study bias, though results for other outcomes did not. Meta regression analyses revealed four significant predictors of intervention effects on depression were found: (1) an aim to treat type-A behaviours (ß = -0.32, p = 0.03) were more effective than other interventions. In contrast, interventions which (2) aimed to educate patients about cardiac risk factors (ß = 0.23, p = 0.03), (3) included client-led discussion and emotional support as core therapeutic components (ß = 0.31, p < 0.01), or (4) included family members in the treatment process (ß = 0.26, p < 0.01) were significantly less effective., Authors' Conclusions: Psychological treatments appear effective in treating psychological symptoms of CHD patients. Uncertainly remains regarding the subgroups of patients who would benefit most from treatment and the characteristics of successful interventions.

Background: Although meta-analyses of randomized controlled trials (RCTs) of salt reduction report a reduction in the level of blood pressure (BP), the effect of reduced dietary salt on cardiovascular disease (CVD) events remains unclear., Methods: We searched for RCTs with follow-up of at least 6 months that compared dietary salt reduction (restricted salt dietary intervention or advice to reduce salt intake) to control/no intervention in adults, and reported mortality or CVD morbidity data. Outcomes were pooled at end of trial or longest follow-up point., Results: Seven studies were identified: three in normotensives, two in hypertensives, one in a mixed population of normo- and hypertensives and one in heart failure. Salt reduction was associated with reductions in urinary salt excretion of between 27 and 39 mmol/24 h and reductions in systolic BP between 1 and 4 mm Hg. Relative risks (RRs) for all-cause mortality in normotensives (longest follow-up-RR: 0.90, 95% confidence interval (CI): 0.58-1.40, 79 deaths) and hypertensives (longest follow-up RR 0.96, 0.83-1.11, 565 deaths) showed no strong evidence of any effect of salt reduction CVD morbidity in people with normal BP (longest follow-up: RR 0.71, 0.42-1.20, 200 events) and raised BP at baseline (end of trial: RR 0.84, 0.57-1.23, 93 events) also showed no strong evidence of benefit. Salt restriction increased the risk of all-cause mortality in those with heart failure (end of trial RR 2.59, 1.04-6.44, 21 deaths).We found no information on participant's health-related quality of life., Conclusions: Despite collating more event data than previous systematic reviews of RCTs (665 deaths in some 6,250 participants) there is still insufficient power to exclude clinically important effects of reduced dietary salt on mortality or CVD morbidity. Our estimates of benefits from dietary salt restriction are consistent with the predicted small effects on clinical events attributable to the small BP reduction achieved.

Background: An earlier Cochrane review of dietary advice identified insufficient evidence to assess effects of reduced salt intake on mortality or cardiovascular events., Objectives: 1. To assess the long term effects of interventions aimed at reducing dietary salt on mortality and cardiovascular morbidity.2. To investigate whether blood pressure reduction is an explanatory factor in any effect of such dietary interventions on mortality and cardiovascular outcomes., Search Strategy: The Cochrane Library (CENTRAL, Health Technology Assessment (HTA) and Database of Abstracts of Reviews of Effect (DARE)), MEDLINE, EMBASE, CINAHL and PsycInfo were searched through to October 2008. References of included studies and reviews were also checked. No language restrictions were applied., Selection Criteria: Trials fulfilled the following criteria: (1) randomised with follow up of at least six-months, (2) intervention was reduced dietary salt (restricted salt dietary intervention or advice to reduce salt intake), (3) adults, (4) mortality or cardiovascular morbidity data was available. Two reviewers independently assessed whether studies met these criteria., Data Collection and Analysis: Data extraction and study validity were compiled by a single reviewer, and checked by a second. Authors were contacted where possible to obtain missing information. Events were extracted and relative risks (RRs) and 95% CIs calculated., Main Results: Seven studies (including 6,489 participants) met the inclusion criteria - three in normotensives (n=3518), two in hypertensives (n=758), one in a mixed population of normo- and hypertensives (n=1981) and one in heart failure (n=232) with end of trial follow-up of seven to 36 months and longest observational follow up (after trial end) to 12.7 yrs. Relative risks for all cause mortality in normotensives (end of trial RR 0.67, 95% CI: 0.40 to 1.12, 60 deaths; longest follow up RR 0.90, 95% CI: 0.58 to 1.40, 79 deaths) and hypertensives (end of trial RR 0.97, 95% CI: 0.83 to 1.13, 513 deaths; longest follow up RR 0.96, 95% CI; 0.83 to 1.11, 565 deaths) showed no strong evidence of any effect of salt reduction. Cardiovascular morbidity in people with normal blood pressure (longest follow-up RR 0.71, 95% CI: 0.42 to 1.20, 200 events) or raised blood pressure at baseline (end of trial RR 0.84, 95% CI: 0.57 to 1.23, 93 events) also showed no strong evidence of benefit. Salt restriction increased the risk of all-cause death in those with congestive heart failure (end of trial relative risk: 2.59, 95% 1.04 to 6.44, 21 deaths). We found no information on participants health-related quality of life., Authors' Conclusions: Despite collating more event data than previous systematic reviews of randomised controlled trials (665 deaths in some 6,250 participants), there is still insufficient power to exclude clinically important effects of reduced dietary salt on mortality or cardiovascular morbidity in normotensive or hypertensive populations. Further RCT evidence is needed to confirm whether restriction of sodium is harmful for people with heart failure. Our estimates of benefits from dietary salt restriction are consistent with the predicted small effects on clinical events attributable to the small blood pressure reduction achieved.

Background: The burden of coronary heart disease (CHD) worldwide is one of great concern to patients and healthcare agencies alike. Exercise-based cardiac rehabilitation aims to restore patients with heart disease to health., Objectives: To determine the effectiveness of exercise-based cardiac rehabilitation (exercise training alone or in combination with psychosocial or educational interventions) on mortality, morbidity and health-related quality of life of patients with CHD., Search Strategy: RCTs have been identified by searching CENTRAL, HTA, and DARE (using The Cochrane Library Issue 4, 2009), as well as MEDLINE (1950 to December 2009), EMBASE (1980 to December 2009), CINAHL (1982 to December 2009), and Science Citation Index Expanded (1900 to December 2009)., Selection Criteria: Men and women of all ages who have had myocardial infarction (MI), coronary artery bypass graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA), or who have angina pectoris or coronary artery disease defined by angiography., Data Collection and Analysis: Studies were selected and data extracted independently by two reviewers. Authors were contacted where possible to obtain missing information., Main Results: This systematic review has allowed analysis of 47 studies randomising 10,794 patients to exercise-based cardiac rehabilitation or usual care. In medium to longer term (i.e. 12 or more months follow-up) exercise-based cardiac rehabilitation reduced overall and cardiovascular mortality [RR 0.87 (95% CI 0.75, 0.99) and 0.74 (95% CI 0.63, 0.87), respectively], and hospital admissions [RR 0.69 (95% CI 0.51, 0.93)] in the shorter term (< 12 months follow-up) with no evidence of heterogeneity of effect across trials. Cardiac rehabilitation did not reduce the risk of total MI, CABG or PTCA. Given both the heterogeneity in outcome measures and methods of reporting findings, a meta-analysis was not undertaken for health-related quality of life. In seven out of 10 trials reporting health-related quality of life using validated measures was there evidence of a significantly higher level of quality of life with exercise-based cardiac rehabilitation than usual care., Authors' Conclusions: Exercise-based cardiac rehabilitation is effective in reducing total and cardiovascular mortality (in medium to longer term studies) and hospital admissions (in shorter term studies) but not total MI or revascularisation (CABG or PTCA). Despite inclusion of more recent trials, the population studied in this review is still predominantly male, middle aged and low risk. Therefore, well-designed, and adequately reported RCTs in groups of CHD patients more representative of usual clinical practice are still needed. These trials should include validated health-related quality of life outcome measures, need to explicitly report clinical events including hospital admission, and assess costs and cost-effectiveness.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of rituximab for the first-line treatment of chronic lymphocytic leukaemia (CLL) based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer's searches for clinical effectiveness and cost-effectiveness data were appropriate and included all relevant studies. The submission's evidence came from a single, unpublished, well-conducted randomised controlled trial (RCT) comparing rituximab in combination with fludarabine and cyclophosphamide (R-FC) with fludarabine and cyclophosphamide (FC) alone for the first-line treatment of CLL. There was a statistically significant increase in progression-free survival (PFS) with R-FC compared with FC alone {median 39.8 months vs 32.2 months; hazard ratio [HR] 0.56 [95% confidence interval (CI) 0.43 to 0.72]}. However, the initial significant treatment benefit for R-FC compared with FC for overall survival was not maintained at a slightly longer follow-up time [median 25.4 months; adjusted HR 0.72 (95% CI 0.48 to 1.09)]. Response rates, numbers of patients with event-free survival and duration of response all favoured treatment with R-FC. Additional evidence from a mixed-treatment comparison model indicated R-FC to be significantly superior to chlorambucil alone for both PFS and overall and complete response rates. The incidence of grade 3 or 4 adverse events was higher in the R-FC arm (77%) than in the FC arm (62%). Dose modifications were also more frequent in this arm, but this did not lead to differences in treatment discontinuation. Roche used a three-state Markov model (PFS, progressed and death) to model the cost-effectiveness of R-FC compared with FC and chlorambucil alone. The model used a cycle length of 1 month and a lifetime time horizon. The approach taken to modelling was reasonable and the sources and justification of estimates were generally sound. The base-case analysis produced an incremental cost-effectiveness ratio (ICER) of 13,189 pounds per quality-adjusted life-year (QALY) for R-FC versus FC, and 6422 pounds per QALY for the comparison of R-FC versus chlorambucil, suggesting that R-FC is cost-effective at normal willingness-to-pay thresholds. One-way sensitivity analyses produced a range of ICERs from 10,249 pounds to 22,661 pounds per QALY for R-FC versus FC, and 5612 pounds and 6921 pounds per QALY for R-FC versus chlorambucil. Probabilistic sensitivity analysis results matched the deterministic results very closely. However, the sensitivity analysis did not fully investigate the uncertainty associated with differential values across arms or with the structural assumptions of the model, and utility values were not drawn from an empirical study. The NICE guidance issued as a result of the STA states that: Rituximab in combination with fludarabine and cyclophosphamide (R-FC) is recommended as an option for the first-line treatment of chronic lymphocytic leukaemia in people for whom fludarabine in combination with cyclophosphamide (FC) is considered appropriate. Rituximab in combination with chemotherapy agents other than fludarabine and cyclophosphamide is not recommended for the first-line treatment of chronic lymphocytic leukaemia.

This paper represents a summary of the evidence review group (ERG) report into the clinical efficacy, safety and cost-effectiveness of everolimus plus best supportive care (BSC) for the treatment of advanced renal cell carcinoma (RCC) which has progressed following or on vascular endothelial growth factor-targeted therapy (sunitinib, sorafenib, bevacizumab), compared to BSC alone. The submitting manufacturer's case for clinical effectiveness and cost-effectiveness was mainly based on a well-conducted randomised controlled trial (RCT), Renal Cell Cancer Treatment with Oral RAD001 Given Daily-1 (RECORD-1), comparing BSC plus everolimus with BSC plus placebo and a de novo economic model. The RCT indicated a marked statistically significant effect on progression-free survival. The base-case incremental cost-effectiveness ratio (ICER) estimate was 52,000 pounds per quality-adjusted life-year (this included a reduction in drug cost associated with an approved patient access scheme). The ERG undertook a critical appraisal of the submission. The ERG was generally in agreement with the submitting manufacturer concerning its estimates of effectiveness; however, there was greater concern surrounding the estimates of cost-effectiveness. The ERG judged that if potential errors in the model were corrected, the ICERs offered by the submitting manufacturer would overstate the cost-effectiveness of everolimus for the second-line treatment of metastatic RCC (that this ICER would be a higher value). Concerning the estimates of cost-effectiveness in RCC, the observations in the ERG report provide strong further support for research collecting rigorous estimates of utilities associated with the main health states likely to be experienced by patients with renal cell cancer. At the time of writing, NICE was yet to issue the Appraisal Consultation Document for this appraisal.

Background: Order communication systems (OCS) are computer applications used to enter diagnostic and therapeutic patient care orders and to view test results. Many potential benefits of OCS have been identified including improvements in clinician ordering patterns, optimisation of clinical time, and aiding communication processes between clinicians and different departments. Many OCS now include computerised decision support systems (CDSS), which are information systems designed to improve clinical decision-making. CDSS match individual patient characteristics to a computerised knowledge base, and software algorithms generate patient-specific recommendations., Objectives: To investigate which CDSS in OCS are in use within the UK and the impact of CDSS in OCS for diagnostic, screening or monitoring test ordering compared to OCS without CDSS. To determine what features of CDSS are associated with clinician or patient acceptance of CDSS in OCS and what is known about the cost-effectiveness of CDSS in diagnostic, screening or monitoring test OCS compared to OCS without CDSS., Data Sources: A generic search to identify potentially relevant studies for inclusion was conducted using MEDLINE, EMBASE, Cochrane Controlled Trials Register (CCTR), CINAHL (Cumulative Index to Nursing and Allied Health Literature), DARE (Database of Abstracts of Reviews of Effects), Health Technology Assessment (HTA) database, IEEE (Institute of Electrical and Electronic Engineers) Xplore digital library, NHS Economic Evaluation Database (NHS EED) and EconLit, searched between 1974 and 2009 with a total of 22,109 titles and abstracts screened for inclusion., Review Methods: CDSS for diagnostic, screening and monitoring test ordering OCS in use in the UK were identified through contact with the 24 manufacturers/suppliers currently contracted by the National Project for Information Technology (NpfIT) to provide either national or specialist decision support. A generic search to identify potentially relevant studies for inclusion in the review was conducted on a range of medical, social science and economic databases. The review was undertaken using standard systematic review methods, with studies being screened for inclusion, data extracted and quality assessed by two reviewers. Results were broadly grouped according to the type of CDSS intervention and study design where possible. These were then combined using a narrative synthesis with relevant quantitative results tabulated., Results: Results of the studies included in review were highly mixed and equivocal, often both within and between studies, but broadly showed a beneficial impact of the use of CDSS in conjunction with OCS over and above OCS alone. Overall, if the findings of both primary and secondary outcomes are taken into account, then CDSS significantly improved practitioner performance in 15 out of 24 studies (62.5%). Only two studies covered the cost-effectiveness of CDSS: a Dutch study reported a mean cost decrease of 3% for blood tests orders (639 euros) in each of the intervention clinics compared with a 2% (208 euros) increase in control clinics in test costs; and a Spanish study reported a significant increase in the cost of laboratory tests from 41.8 euros per patient per annum to 47.2 euros after implementation of the system., Limitations: The response rate from the survey of manufacturers and suppliers was extremely low at only 17% and much of the feedback was classified as being commercial-in-confidence (CIC). No studies were identified which assessed the features of CDSS that are associated with clinician or patient acceptance of CDSS in OCS in the test ordering process and only limited data was available on the cost-effectiveness of CDSS plus OCS compared with OCS alone and the findings highly specific. Although CDSS appears to have a potentially small positive impact on diagnostic, screening or monitoring test ordering, the majority of studies come from a limited number of institutions in the USA., Conclusions: If the findings of both primary and secondary outcomes are taken into account then CDSS showed a statistically significant benefit on either process or practitioner performance outcomes in nearly two-thirds of the studies. Furthermore, in four studies that assessed adverse effects of either test cancellation or delay, no significant detrimental effects in terms of additional utilisation of health-care resources or adverse events were observed. We believe the key current need is for a well designed and comprehensive survey, and on the basis of the results of this potentially for evaluation studies in the form of cluster randomised controlled trials or randomised controlled trials which incorporate process, and patient outcomes, as well as full economic evaluations alongside the trials to assess the impact of CDSS in conjunction with OCS versus OCS alone for diagnostic, screening or monitoring test ordering in the NHS. The economic evaluation should incorporate the full costs of potentially developing, testing, and installing the system, including staff training costs., Study Registration: Study registration 61.

Background: Cardiac rehabilitation is an important component of recovery from coronary events but uptake and adherence to such programmes are below the recommended levels. This aim is to update a previous non-Cochrane systematic review which examined interventions that may potentially improve cardiac patient uptake and adherence in rehabilitation or its components and concluded that there is insufficient evidence to make specific recommendations., Objectives: To determine the effects of interventions to increase patient uptake of, and adherence to, cardiac rehabilitation., Search Strategy: A previous systematic review identified studies published prior to June 2001. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 4 2007), MEDLINE (2001 to January 2008), EMBASE (2001 to January 2008), CINAHL (2001 to January 2008), PsycINFO (2001 to January 2008), Web of Science: ISI Proceedings (2001 to April 2008), and NHS Centre for Reviews and Dissemination (CRD) databases (Health Technology Assessment (HTA) and Database of Abstracts of Reviews of Effects (DARE)) from 2001 to January 2008. Reference lists of identified systematic reviews and randomised control trials (RCTs) were also checked for additional studies., Selection Criteria: Adults with myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, heart failure, angina, or coronary heart disease eligible for cardiac rehabilitation and randomised or quasi-randomised trials of interventions to increase uptake or adherence to cardiac rehabilitation or any of its component parts. Only studies reporting a measure of adherence were included., Data Collection and Analysis: Titles and abstracts of all identified references were screened for eligibility by two reviewers independently and full papers of potentially relevant trials were obtained and checked. Included studies were assessed for risk of bias by two reviewers., Main Results: Ten studies were identified, three of interventions to improve uptake of cardiac rehabilitation and seven of interventions to increase adherence. Meta-analysis was not possible due to multiple sources of heterogeneity. All three interventions targeting uptake of cardiac rehabilitation were effective. Two of seven studies intended to increase adherence had a significant effect. Only one study reported the non-significant effects of the intervention on cardiovascular risk factors and no studies reported data on mortality, morbidities, costs or health care resource utilisation., Authors' Conclusions: There is some evidence to suggest that interventions to increase the uptake of cardiac rehabilitation can be effective. Few practice recommendations for increasing adherence to cardiac rehabilitation can be made at this time. Interventions targeting patient identified barriers may increase the likelihood of success. Further high quality research is needed.

Aims: To determine the effect of exercise training on clinical events and health-related quality of life (HRQoL) of patients with systolic heart failure., Methods and Results: We searched electronic databases including Medline, EMBASE, and Cochrane Library up to January 2008 to identify randomized controlled trials (RCTs) comparing exercise training and usual care with a minimum follow-up of 6 months. Nineteen RCTs were included with a total of 3647 patients, the majority of whom were male, low-to-medium risk, and New York Heart Association class II-III with a left ventricular ejection fraction of <40%. There was no significant difference between exercise and control in short-term (

Background: From previous systematic reviews and meta-analyses there is consensus about the positive effect of exercise training on exercise capacity; however, the effects on health-related quality of life, mortality and hospital admissions in heart failure remain uncertain., Objectives: To update the previous systematic review which determined the effectiveness of exercise-based interventions on the mortality, hospitalisation admissions, morbidity and health-related quality of life for patients with systolic heart failure., Search Strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 4). To update searches from the previous review, MEDLINE, EMBASE, CINAHL, and PsycINFO were searched (2001 to January 2008). ISI Proceedings and bibliographies of identified reviews were checked., Selection Criteria: Randomised controlled trials of exercise-based interventions with six months follow up or longer compared to usual medical care or placebo. The study population comprised adults of all ages (> 18 years) with evidence of chronic systolic heart failure., Data Collection and Analysis: All identified references were independently screened by two review authors and those that were clearly ineligible were rejected. Full papers of potentially relevant trials were obtained. Data were independantly extracted from the included trials and their risk of bias assessed by a single review author and checked by a second., Main Results: Nineteen trials (3647 participants) met the inclusion criteria. One large trial recuited 2331 of the participants. There was no significant difference in pooled mortality between groups in the 13 trials with < 1 year follow up. There was evidence of a non-significant trend toward a reduction in pooled mortality with exercise in the four trials with > 1 year follow up. A reduction in the hospitalisation rate was demonstrated with exercise training programmes. Hospitalisations due to systolic heart failure were reduced with exercise and there was a significant improvement in health-related quality of life (HRQoL). The effect of cardiac exercise training on total mortality and HRQoL were independent of the degree of left ventricular dysfunction, type of cardiac rehabilitation, dose of exercise intervention, length of follow up, trial quality, and trial publication date., Authors' Conclusions: The previous version of this review showed that exercise training improved exercise capacity in the short term in patients with mild to moderate heart failure when compared to usual care. This updated review provides evidence that in a similar population of patients, exercise does not increase the risk of all-cause mortality and may reduce heart failure-related hospital admissions. Exercise training may offer important improvements in patients' health-related quality of life.

Skin cancer is an increasing problem in Europe, America and Australasia, although largely preventable by avoiding excessive ultraviolet (UV) exposure. This paper presents the findings of a systematic review of qualitative research about the prevention of skin cancer attributable to UV exposure. The aim is to understand elements that may contribute to the successful or unsuccessful conveyance of skin cancer prevention messages and their uptake by the public. A systematic review was undertaken using evidence identified through searching electronic bibliographic databases and Web sites and reference list checks. Predefined inclusion and exclusion criteria were used. Sixteen study reports (relating to 15 separate studies) were included from the United Kingdom, United States, Australia, Canada and New Zealand. Each included study was quality appraised, and the findings were extracted into an evidence table. A coding scheme, framed by the Health Belief Model, was developed by the reviewers and informed analysis and synthesis. This showed that most people perceived their susceptibility to skin cancer, and its severity, as low. While benefits of adopting changed behaviour were acknowledged, there were substantial barriers to this, including positive perceptions of a tan as healthy and attractive and the hassle of covering up or using sunscreen. Peers, parents and media may offer 'cues to action' that encourage adoption of preventative behaviour and finally self-efficacy or the perceived ability to make such changes. Effective health education messages will need to address the barriers to adopting protective behaviours identified through this review.

Background: The burden of cardiovascular disease world-wide is one of great concern to patients and health care agencies alike. Traditionally centre-based cardiac rehabilitation (CR) programmes are offered to individuals after cardiac events to aid recovery and prevent further cardiac illness. Home-based cardiac rehabilitation programmes have been introduced in an attempt to widen access and participation., Objectives: To determine the effectiveness of home-based cardiac rehabilitation programmes compared with supervised centre-based cardiac rehabilitation on mortality and morbidity, health-related quality of life and modifiable cardiac risk factors in patients with coronary heart disease., Search Strategy: We updated the search of a previous review by searching the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2007, Issue 4), MEDLINE, EMBASE and CINAHL from 2001 to January 2008. We checked reference lists and sought advice from experts. No language restrictions were applied., Selection Criteria: Randomised controlled trials (RCTs) that compared centre-based cardiac rehabilitation (e.g. hospital, gymnasium, sports centre) with home-based programmes, in adults with myocardial infarction, angina, heart failure or who had undergone revascularisation., Data Collection and Analysis: Studies were selected independently by two reviewers, and data extracted by a single reviewer and checked by a second one. Authors were contacted where possible to obtain missing information., Main Results: Twelve studies (1,938 participants) met the inclusion criteria. The majority of studies recruited a lower risk patient following an acute myocardial infarction (MI) and revascularisation. There was no difference in outcomes of home- versus centre-based cardiac rehabilitation in mortality risk ratio (RR) was1.31 (95% confidence interval (C) 0.65 to 2.66), cardiac events, exercise capacity standardised mean difference (SMD) -0.11 (95% CI -0.35 to 0.13), as well as in modifiable risk factors (systolic blood pressure; diastolic blood pressure; total cholesterol; HDL-cholesterol; LDL-cholesterol) or proportion of smokers at follow up or health-related quality of life. There was no consistent difference in the healthcare costs of the two forms of cardiac rehabilitation., Authors' Conclusions: Home- and centre-based cardiac rehabilitation appear to be equally effective in improving the clinical and health-related quality of life outcomes in acute MI and revascularisation patients. This finding, together with an absence of evidence of difference in healthcare costs between the two approaches, would support the extension of home-based cardiac rehabilitation programmes such as the Heart Manual to give patients a choice in line with their preferences, which may have an impact on uptake of cardiac rehabilitation in the individual case.

Objective: To compare the effect of home based and supervised centre based cardiac rehabilitation on mortality and morbidity, health related quality of life, and modifiable cardiac risk factors in patients with coronary heart disease., Design: Systematic review., Data Sources: Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Medline, Embase, CINAHL, and PsycINFO, without language restriction, searched from 2001 to January 2008., Review Methods: Reference lists checked and advice sought from authors. Included randomised controlled trials that compared centre based cardiac rehabilitation with home based programmes in adults with acute myocardial infarction, angina, or heart failure or who had undergone coronary revascularisation. Two reviewers independently assessed the eligibility of the identified trials and extracted data independently. Authors were contacted when possible to obtain missing information., Results: 12 studies (1938 participants) were included. Most studies recruited patients with a low risk of further events after myocardial infarction or revascularisation. No difference was seen between home based and centre based cardiac rehabilitation in terms of mortality (relative risk 1.31, 95% confidence interval 0.65 to 2.66), cardiac events, exercise capacity (standardised mean difference -0.11, -0.35 to 0.13), modifiable risk factors (weighted mean difference systolic blood pressure (0.58 mm Hg, -3.29 mm Hg to 4.44 mm Hg), total cholesterol (-0.13 mmol/l, -0.31 mmol/l to 0.05 mmol/l), low density lipoprotein cholesterol (-0.15 mmol/l, -0.31 mmol/l to 0.01 mmol/l), or relative risk for proportion of smokers at follow-up (0.98, 0.73 to 1.31)), or health related quality of life, with the exception of high density lipoprotein cholesterol (-0.06, -0.11 to -0.02) mmol/l). In the home based participants, there was evidence of superior adherence. No consistent difference was seen in the healthcare costs of the two forms of cardiac rehabilitation., Conclusions: Home and centre based forms of cardiac rehabilitation seem to be equally effective in improving clinical and health related quality of life outcomes in patients with a low risk of further events after myocardial infarction or revascularisation. This finding, together with the absence of evidence of differences in patients' adherence and healthcare costs between the two approaches, supports the further provision of evidence based, home based cardiac rehabilitation programmes such as the "Heart Manual." The choice of participating in a more traditional supervised centre based or evidence based home based programme should reflect the preference of the individual patient.

Objectives: To estimate the cost-effectiveness of temsirolimus compared to interferon-alpha for first line treatment of patients with advanced, poor prognosis renal cell carcinoma, from the perspective of the UK National Health Service., Methods: A decision-analytic model was developed to estimate the cost-effectiveness of temsirolimus. The clinical effectiveness of temsirolimus compared with interferon-alpha and the utility values (using EQ-5D tariffs) were taken from a recent phase III randomized clinical trial. Cost data were obtained from published literature and based on current UK practice. The effect of parameter uncertainty on cost-effectiveness was explored through extensive one-way and probabilistic sensitivity analyses., Results: Compared to interferon-alpha, temsirolimus treatment resulted in an incremental cost per QALY gained of pound94,632; based on an estimated mean gain of 0.24 quality-adjusted life years (QALYs) per patient, at a mean additional cost of pound22,331 (inflated to 2007/8). The cost per QALY for patient subgroups ranged from pound74,369 to pound154,752. The probability that temsirolimus is cost-effective compared to interferon-alpha at a willingness to pay threshold of pound30,000 per QALY for all patient groups is expected to be close to zero. The cost per QALY was sensitive to the clinical effectiveness parameters, health state utilities, drug costs and the cost of administration of temsirolimus., Conclusions: Temsirolimus has been shown to be clinically effective compared to interferon-alpha offering additional health benefits, however, with a cost per QALY in excess of pound90,000, it may not be regarded as a cost-effective use of resources in some health care settings.

Objectives: To estimate the cost-effectiveness of sorafenib (Nexavar, Bayer, Leverkusen, Germany) versus best supportive care (BSC) for second-line treatment of advanced renal cell carcinoma from the perspective of the UK National Health Service., Methods: A decision analytic model was developed to estimate the cost-effectiveness of sorafenib. The clinical effectiveness of sorafenib versus BSC was taken from a recent randomized phase III trial. Utility values were taken from a phase II trial of sunitinib, using EQ-5D tariffs. Cost data were obtained from published literature and were based on current UK practice. The effect of parameter uncertainty on cost-effectiveness was explored through extensive one-way and probabilistic sensitivity analyses., Results: Compared to BSC, sorafenib treatment resulted in an incremental cost per quality-adjusted life year (QALY) gained of pound75,398, based on an estimated mean gain of 0.27 QALYs per patient, at a mean additional cost of pound20,063 (inflated to 2007/2008). The probability that sorafenib is cost-effective compared to BSC at a willingness to pay threshold of pound30,000 per QALY is 0.0%. In sensitivity analysis, estimates of cost per QALY were sensitive to changes in the clinical effectiveness parameters, and to health state utilities and drug costs., Conclusions: Sorafenib has been shown to be clinically effective compared to BSC, offering additional health benefits; however, with a cost per QALY in excess of pound70,000, it may not be regarded as a cost-effective use of resources in some health-care settings.

Objectives: To assess the clinical effectiveness and cost-effectiveness of bevacizumab, combined with interferon (IFN), sorafenib tosylate, sunitinib and temsirolimus in the treatment of people with advanced and/or metastatic renal cell carcinoma (RCC)., Data Sources: Electronic databases, including MEDLINE, EMBASE and the Cochrane Library, were searched up to September/October 2007 (and again in February 2008)., Review Methods: Systematic reviews and randomised clinical trials comparing any of the interventions with any of the comparators in participants with advanced and/or metastatic RCC were included, also phase II studies and conference abstracts if there was sufficient detail to adequately assess quality. Results were synthesised narratively and a decision-analytic Markov-type model was developed to simulate disease progression and estimate the cost-effectiveness of the interventions under consideration., Results: A total of 888 titles and abstracts were retrieved in the clinical effectiveness review, including reports of eight clinical trials. Treatment with bevacizumab plus IFN or sunitinib had clinically relevant and statistically significant advantages over treatment with IFN alone, in terms of progression-free survival and tumour response, doubling median progression-free survival from approximately 5 months to 10 months. Temsirolimus had similar advantages over treatment with IFN in terms of progression-free and overall survival, increasing median overall survival from 7.3 to 10.9 months [hazard ratio (HR) 0.73; 95% confidence interval (CI) 0.58 to 0.92)], as did sorafenib in comparison with best supportive care in terms of overall survival, progression-free survival and tumour response, with a doubling of progression-free survival (HR 0.51; 95% CI 0.43 to 0.60). However, the last was associated with an increased frequency of hypertension and hand-foot skin reaction compared with placebo. No fully published economic evaluations of any of the interventions could be located. However, estimates from the PenTAG model suggested that none of the interventions would be considered cost-effective at a willingness-to-pay threshold of 30,000 pounds per quality-adjusted life-year (QALY). Estimates of cost per QALY ranged from 71,462 pounds for sunitinib to 171,301 pounds for bevacizumab plus IFN. Although there are many similarities in the methodology and structural assumptions employed by PenTAG and the manufacturers of the interventions, in all cases the cost-effectiveness estimates from the PenTAG model were higher than those presented in the manufacturers' submissions. Cost-effectiveness estimates were particularly sensitive to variations in the estimates of treatment effectiveness, drug pricing (including dose intensity data), and health-state utility input parameters., Conclusions: Treatment with bevacizumab plus IFN and sunitinib has clinically relevant and statistically significant advantages over treatment with IFN alone in patients with metastatic RCC. In people with three of six risk factors for poor prognosis, temsirolimus had clinically relevant advantages over treatment with IFN, and sorafenib tosylate was superior to best supportive care as second-line therapy. The frequency of adverse events associated with bevacizumab plus IFN, sunitinib and temsirolimus was comparable with that seen with IFN, although the adverse event profile is different. Treatment with sorafenib was associated with a significantly increased frequency of hypertension and hand-foot syndrome. Estimates from the PenTAG model suggested that none of the interventions would be considered cost-effective at a willingness-to-pay threshold of 30,000 pounds per QALY.

The submission's evidence for the clinical effectiveness and cost-effectiveness of sunitinib for the treatment of gastrointestinal stromal tumours (GISTs) is based on a randomised controlled trial (RCT) comparing sunitinib with placebo for people with unresectable and/or metastatic GIST after failure of imatinib and with Eastern Cooperative Oncology Group (ECOG) progression status 0-1, and an ongoing, non-comparative cohort study of a similar population but with ECOG progression status 0-4. The searches are appropriate and include all relevant studies and the RCT is of high quality. In the RCT sunitinib arm overall survival was 73 median weeks [95% confidence interval (CI) 61 to 83] versus 75 median weeks (95% CI 68 to 84) for the cohort study. However, time to tumour progression in the cohort study was different from that in the RCT sunitinib arm [41 (95% CI 36 to 47) versus 29 (95% CI 22 to 41) median weeks respectively]. Median progression-free survival with sunitinib was 24.6 weeks (95% CI 12.1 to 28.4) versus 6.4 weeks (95% CI 4.4 to 10.0) on placebo (hazard ratio 0.333, 95% CI 0.238 to 0.467, p < 0.001). The manufacturer used a three-state Markov model to model the cost-effectiveness of sunitinib compared with best supportive care for GIST patients; the modelling approach and sources and justification of estimates are reasonable. The base-case incremental cost-effectiveness ratio (ICER) was 27,365 pounds per quality-adjusted life-year (QALY) with the first cycle of sunitinib treatment not costed; when we included the cost of the first treatment cycle we estimated a base-case ICER of 32,636 pounds per QALY. Pfizer's sensitivity analysis produced a range of ICERs from 15,536 pounds per QALY to 59,002 pounds per QALY. Weaknesses of the manufacturer's submission include that the evidence is based on only one published RCT; that 84% of the RCT control population crossed over to the intervention group, giving rise to the use of unusual rank preserved structural failure time (RPSFT) analysis to correct for possible bias; and that a number of errors and omissions were made in the probabilistic sensitivity analysis, meaning that it is not possible to come to firm conclusions about the cost-effectiveness of sunitinib for GIST in this patient population. In conclusion, during the blinded phase of the RCT, overall survival was significantly longer in the sunitinib arm than in the placebo arm (hazard ratio 0.491, 95% CI 0.290 to 0.831, p <0.007). However, intention-to-treat analysis of the entire study showed no statistically significant difference in overall survival for those who received sunitinib (73 weeks) versus those who received placebo (65 weeks) (hazard ratio 0.876, 95% CI 0.679 to 1.129, p = 0.306).