'Cut down to quit' with nicotine replacement therapies in smoking cessation: a systematic review of effectiveness and economic analysis.

OBJECTIVES: To examine the effectiveness and cost-effectiveness of nicotine replacement therapy (NRT) for 'cut down to quit' (CDTQ) smoking. DATA SOURCES: Major electronic databases were searched up to July 2006. REVIEW METHODS: Data from studies meeting the criteria were reviewed and analysed. A decision analytical model was constructed to estimate the cost-effectiveness of CDTQ from the NHS perspective. RESULTS: No systematic reviews of the effectiveness of CDTQ and no randomised controlled trials (RCTs) specifically addressing CDTQ were identified. Seven randomised placebo-controlled trials satisfied the inclusion criteria; six of these were industry sponsored. However, sustained smoking cessation was only reported as a secondary outcome in these trials and required commencement of cessation within the first 6 weeks of treatment. Meta-analyses of the study level results demonstrated statistically significant superiority of NRT compared with placebo. Individual patient data from unpublished reports of five RCTs were used to calculate sustained abstinence of at least 6 months starting at any time during the treatment period (generally 12 months). From this the meta-analysis indicated statistically significant superiority of NRT versus placebo [relative risk 2.06, 95% confidence interval (CI) 1.34 to 3.15]. The proportions achieving this outcome across all five RCTs were 6.75% of participants in receipt of NRT and 3.29% of those receiving placebo. The number-needed-to-treat was 29. This measure of sustained abstinence was used for economic modelling. No existing economic analyses of CDTQ were identified. A de novo decision analytic model was constructed to estimate the cost-effectiveness of making CDTQ with NRT available for smokers unwilling or unable to attempt an abrupt quit. The outcome measure was expected quality-adjusted life-years (QALYs). The model results suggest that CDTQ with NRT delivers incremental cost-effectiveness ratios (ICERs) ranging from around 1500 pounds/QALY to 7700 pounds/QALY depending on the age at which smoking cessation was achieved and the modes of CDTQ delivery. Assuming applicability to a single population, CDTQ was not cost-effective compared with abrupt quitting. If CDTQ with NRT were to be offered on the NHS as a matter of policy, the base-case results suggest that it would only be effective and cost-effective if a substantial majority of the people attempting CDTQ with NRT were those who would otherwise make no attempt to quit. This result is robust to considerable variation in the forms of CDTQ with NRT offered, and to the assumptions about QALY gained per quit success. CONCLUSIONS: Meta-analysis of RCT evidence of quit rates in NRT-supported smoking reduction studies indicates that NRT is an effective intervention in achieving sustained smoking abstinence for smokers who declare unwillingness or inability to attempt an abrupt quit. The 12-month sustained abstinence success rate in this population (approximately 5.3% with NRT versus approximately 2.6% with placebo) is considerably less than that documented for an abrupt quit NRT regime in smokers willing to attempt an abrupt quit with NRT (which according to other systematic reviews is around 16% with NRT versus 10% with placebo). Most of the evidence of effectiveness of CDTQ came from trials that required considerable patient-investigator contact. Therefore, for CDTQ with NRT to generate similar abstinence rates for this recalcitrant population in a real-world setting would probably require a similar mode of delivery. The modelling undertaken, which was based on reasonable assumptions about costs, benefits and success rates, suggests that CDTQ is highly cost-effective compared with no quit attempt. CDTQ remains cost-effective if dilution from abrupt quitting forms a small proportion of CDTQ attempts. In an alternative analysis in which smokers who switch from an abrupt quit to CDTQ retain the success rate of abrupt quitters, all forms of CDTQ appear cost-effective. Randomised trials in recalcitrant smokers allowing head-to-head comparison of CDTQ delivered with various modalities would be informative.

Clinical effectiveness and cost-effectiveness of different models of managing long-term oral anticoagulation therapy: a systematic review and economic modelling.

OBJECTIVES: To examine the clinical effectiveness and cost-effectiveness of self-testing and self-management of oral anticoagulation treatment compared with clinic-based monitoring. DATA SOURCES: Major electronic databases were searched up to September 2005. REVIEW METHODS: A systematic review was undertaken of relevant data from selected studies. Results about complication events and deaths were pooled in meta-analyses using risk difference (RD) as the outcome statistic. Heterogeneity across trials and possible publication bias were statistically measured. Subgroup analyses (post hoc) were conducted to compare results of self-testing versus self-management, low versus high trial quality, trials conducted in the UK versus trials in other countries and industry versus other sponsors. A Markov-type, state-transition model was developed. Stochastic simulations using the model were conducted to investigate uncertainty in estimated model parameters. RESULTS: In the 16 randomised and eight non-randomised trials selected, patient self-monitoring of oral anticoagulation therapy was found to be more effective than poor-quality usual care provided by family doctors and as effective as good-quality specialised anticoagulation clinics in maintaining the quality of anticoagulation therapy. There was no significant RD of major bleeding events between patient self-monitoring and usual care controls and pooled analyses found that compared with primary care or anticoagulation control (AC) clinics, self-monitoring was statistically significantly associated with fewer thromboembolic events. However, the reduction in complication events and deaths was not consistently associated with the improvement of AC; in some trials this may be due to alternative explanations, including patient education and patient empowerment. Also, the improved AC and the reduction of major complications and deaths by patient self-monitoring were mainly observed in trials conducted outside the UK. According to UK-specific data, for every 100 eligible patients, 24% would agree to conduct self-monitoring, 17 of the 24 patients (70%) could be successfully trained and able to carry out self-monitoring and only 14 of these (80%) would conduct long-term self-monitoring. Seven cost-effectiveness studies were identified and the study that provided the most relevant UK data found that patient self-management was more expensive than current routine care (417 pounds versus 122 pounds per patient-year) and concluded that using a cost-effectiveness threshold of 30,000 pounds per quality-adjusted life-year (QALY) gained, patient self-management does not appear to be cost-effective. De novo modelling for this report found that the incremental cost per QALY gained by patient self-monitoring is 122,365 pounds over 5 years and 63,655 pounds over 10 years. The estimated probability that patient self-monitoring is cost-effective (up to 30,000 pounds/QALY) is 44% over a 10-year period. Wide adoption of patient self-monitoring of anticoagulation therapy would cost the NHS an estimated additional 8-14 million pounds per year. CONCLUSIONS: For selected and successfully trained patients, self-monitoring is effective and safe for long-term oral anticoagulation therapy. In general, patient self-management (PSM) is unlikely to be more cost-effective than the current specialised anticoagulation clinics in the UK; self-monitoring may enhance the quality of life for some patients who are frequently away from home, who are in employment or education, or those who find it difficult to travel to clinics. Further research is needed into alternative dosing regimes, the clinical effectiveness and cost-effectiveness of patient education and training in long-term oral anticoagulation therapy, UK-relevant cost-effectiveness, the effectiveness of PSM in children, and the potential future developments of near-patient testing devices.

A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry's disease and mucopolysaccharidosis type 1.

OBJECTIVES: To determine the clinical effectiveness and cost-effectiveness of the administration of intravenous enzyme replacement therapy (ERT) to symptomatic patients for the prevention of long-term damage and symptoms in Fabry's disease and in mucopolysaccharidosis type 1 (MPS1). DATA SOURCES: Electronic databases from inception up to mid-2004. Contact with clinical experts. REVIEW METHODS: Relevant studies were identified and assessed using recommended quality criteria. RESULTS: The results suggested beneficial effects of ERT for Fabry's disease on measures of pain, cardiovascular function and some end-points reflecting neurosensory function. Renal function appeared to be stabilised by ERT. At present there are no utility-related health-related quality of life data on which to assess the relative health gain of ERT in MPS1. In order to be able to demonstrate the full extent of health gain from treatment, it was necessary to review the natural history of untreated patients in each disease in order to try to estimate the health loss prevented. The published information for Fabry's disease tallied with descriptions of a multi-system, life-threatening disorder particularly involving kidney, heart and brain with individual patients exhibiting many manifestations. The fragmentary information reviewed in 16 studies relevant to the natural history of MPS1 did not generate a coherent picture of disease progression and could provide little added value to published narrative reviews. For Fabry's disease, the mean cost per patient (50 kg) treated is around pounds sterling 85,000 per annum in England and Wales. The cost per patient varies considerably by dose. No published evidence reporting an economic evaluation of ERT for Fabry's disease was identified by this review. A dynamic decision model was constructed based on a birth cohort of male patients who are followed up until death. Owing to lack of information reported in the literature, many assumptions had to be applied. The key assumptions were that ERT returns patients to full health and a normal life expectancy. As far as possible, all assumptions favoured rather than detracted from the value of ERT. ERT was assumed to restore patients to full health in the base case. The estimated incremental cost-effectiveness ratio (ICER) in the base case was pounds sterling 252,000 per QALY (agalsidase beta). Univariate sensitivity analysis around the key assumptions produced ICERs ranging from pounds sterling 602,000 to pounds sterling 241,000. The base case unit cost of ERT was taken as pounds sterling 65.1/mg based on the cost of agalsidase beta. The unit cost would have had to be reduced to pounds sterling 9 to obtain an ICER of pounds sterling 30,000 per QALY. For MPS1, the mean cost per child patient (20 kg) treated is approximately pounds sterling 95,000 and an adult (70 kg) around pounds sterling 335,000 per annum in England and Wales. The cost per patient varies considerably by dose. There is no published evidence reporting an economic evaluation of ERT for MPS1 and no study was identified that reported the quality of life of MPS1 patients within a utility format. Furthermore, no or minimal information of the severity and rate of change of clinical manifestations of disease or the impact of ERT on these factors was identified. Information on the effect of ERT on mortality is also lacking owing to the relatively short time that the treatment has been available. Given this lack of data, it was not possible to develop a cost-effectiveness model of ERT treatment for MPS1 as the model would consist almost completely of assumptions based on no published evidence, leading to an incremental cost per QALY result that would be meaningless. CONCLUSIONS: Although ERT for treating the 'average' patient with Fabry's disease exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over sixfold, and the value for MPS1 is likely to be of a similar order of magnitude, clinicians and the manufacturers argue that, as the disease is classified as an orphan disease under European Union legislation, it has special status, and the NHS has no option but to provide ERT. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, this was very thin indeed. Nonetheless, even large errors in assumptions made will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. In order to overcome limited evidence on the natural history of the disease and the clinical effectiveness of the intervention, the establishment of disease-specific data registries is suggested to facilitate the process of technology assessment and improving patient care. These registries should attempt to include all affected patients in the UK, and collect longitudinal patient level data on clinically relevant problems, interventions received and quality of life in a utility format.

The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review.

OBJECTIVES: To examine the clinical effectiveness and cost-effectiveness of newer antiepileptic drugs (AEDs) for epilepsy in children: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and vigabatrin. DATA SOURCES: Electronic databases. Drug company submissions. REVIEW METHODS: For the systematic review of clinical and cost-effectiveness, studies were assessed for inclusion according to predefined criteria. Data extraction and quality assessment were also undertaken. A decision-analytic model was constructed to estimate the cost-effectiveness of the newer agents in children with partial seizures, the only condition where there were sufficient trial data to inform a model. RESULTS: The quality of the randomised controlled trial (RCT) data was generally poor. For each of the epilepsy subtypes considered in RCTs identified for this review (partial epilepsy with or without secondary generalisation, Lennox-Gastaut syndrome, infantile spasms, absence epilepsy and benign epilepsy with centrotemporal spikes), there is some evidence from placebo-controlled trials that the newer agents tested are of some value in the treatment of these conditions. Where active controls have been used, the limited evidence available does not indicate a difference in effectiveness between newer and older drugs. The data are not sufficient to inform a prescribing strategy for any of the newer agents in any of these conditions. In particular, there is no clinical evidence to suggest that the newer agents should be considered as a first-choice treatment in any form of epilepsy in children. Annual drug costs of the newer agents ranges from around 400 pound to 1200 pound, depending on age and concomitant medications. An AED that is ineffective or has intolerable side-effects will only be used for a short period of time, and many patients achieving seizure freedom will successfully withdraw from drug treatment without relapsing. The results of the decision-analytic model do not suggest that the use of the newer agents in any of the scenarios considered is clearly cost-effective but, similarly, do not indicate that they are clearly not cost-effective. CONCLUSIONS: The prognosis for children diagnosed with epilepsy is generally good, with a large proportion responding well to the first treatment given. A substantial proportion, however, will not respond well to treatment, and for these patients the clinical goal is to find an optimal balance between the benefits and side-effects of any treatment given. For the newly, or recently, diagnosed population, the key question for the newer drugs is how soon they should be tried. The cost-effectiveness of using these agents early, in place of one of the older agents, will depend on the effectiveness and tolerability of these agents compared with the older agents; the evidence from the available trial data so far suggests that the newer agents are no more effective but may be somewhat better tolerated than the older agents, and so the cost-effectiveness for early use will depend on the trade-off between effectiveness and tolerability, both in terms of overall (long-term) treatment retention and overall utility associated with effects on seizure rate and side-effects. There are insufficient data available to estimate accurately the nature of this trade off either in terms of long-term treatment retention or utility. Better information is required from RCTs before any rational evidence-based prescribing strategy could be developed. Ideally, RCTs should be conducted from a 'public health' perspective, making relevant comparisons and incorporating outcomes of interest to clinicians and patients, with sufficiently long-term follow-up to determine reliably the clinical utility of different treatments, particularly with respect to treatment retention and the balance between effectiveness and tolerability. RCTs should mirror clinical practice with respect to diagnosis, focusing on defined syndromes or, where no syndrome is identified, on groups defined by specific seizure type(s) and aetiology. Epilepsy in children is a complex disease, with a variety of distinct syndromes and many alternative treatment options and outcomes. Diagnosis-specific decision-analytic models are required; further research may be required to inform parameter values adequately with respect to epidemiology and clinical practice.

The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher's disease: a systematic review.

OBJECTIVES: The aim of this review is to determine the clinical effectiveness and cost-effectiveness of enzyme replacement therapy (ERT) in the treatment of symptomatic Gaucher's disease. DATA SOURCES: Major electronic databases were searched from their inception to August 2003; and updated from January 2003 to July/August 2004. REVIEW METHODS: Databases were searched for studies that met the criteria and selected data were extracted and evaluated. Studies were assessed for their relevance to the UK context and the review objective. The bibliographic databases were also searched to identify existing cost studies, economic evaluations and models. A Markov decision model was constructed based on patients moving between states defined by the modified Severity Score Index (SSI). Most of the parameters were derived from the published literature. ERT was assumed to restore patients to full health in the base case. RESULTS: Sixty-three studies were included, all suggestive of benefit with ERT. However, the way in which the effects translate into patient well-being and survival or the need for services and resources has not been reliably estimated. Quality of life improvements with ERT have been reported. Nonetheless, studies based on the Short Form 36 (SF-36) indicate that patients treated with ERT continue to have reduced health-related quality of life (HRQoL) compared with the general population. No study attached utility values to quality of life measures for ERT-treated patients. Thirty-one studies relevant to the natural history of the disease were found. Sixteen looked at multiple clinical characteristics of a cohort of patients with type I Gaucher's disease. There was considerable within-study and between-study heterogeneity, but all showed that Gaucher's disease was a progressive condition. Some suggested that the disease may become more indolent in adulthood; however, studies were discrepant on this point. Most disease is diagnosed in adulthood, although about one-quarter presented in childhood, these patients having the most severe symptoms and greatest rate of progression. Modelling of natural history was undertaken using the five papers that reported the SSI for each patient, along with patient-level data on age, age at diagnosis, splenectomy status and genotype, to address the question of whether disease stabilises in adulthood and the degree of correlation between phenotype and genotype. Analysis of the available data suggested that disease progression is likely to slow markedly in adulthood and that genotype is a useful predictor of clinical expression of the disease. Five studies looked at quality of life. Data on this topic were also obtained from the registries. The evidence suggests that the vast majority of the clinical characteristics of type I Gaucher's disease have little impact on subjective HRQoL and that therefore for the majority of people with type I Gaucher's disease this may not be a severe condition. Bone and skeletal symptoms contribute most to the morbidity of the disease and can lead to severe pain and immobility. The mean cost per patient treated was approximately pounds sterling 86,000 per annum in England and Wales. The cost per patient varied considerably by dose. Four existing economic evaluations were found, all of which calculated a very high cost per quality-adjusted life-year (QALY). Using the Markov decision model, ERT was assumed to restore patients to full health in the base case. The estimated incremental cost per QALY [incremental cost-effectiveness ratio (ICER)] in the base case ranged from pounds sterling 380,000 to pounds sterling 476,000 per QALY, depending on genotype. Univariate sensitivity analyses examined ERT not restoring full health, more severe disease progression in the untreated cohort, and only treating the most severely affected patients. These produced ICERs of approximately pounds sterling 1.4 million, pounds sterling 296,000 and pounds sterling 275,000 per QALY, respectively. The base-case unit cost of the drug is pounds sterling 2.975. The unit cost would have had to be reduced ten-fold, to pounds sterling 0.30, to obtain an ICER of pounds sterling 30,000 per QALY. At a unit cost of pounds sterling 1 the ICER would be pounds sterling 120,000 per QALY. CONCLUSIONS: Although ERT for treating the 'average' Gaucher's disease patient exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over ten-fold, some argue that since orphan drug legislation encouraged the manufacture of Cerezyme, and Gaucher's disease can be defined as an orphan disease, the NHS has little option but to provide it, despite its great expense. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, these were very thin indeed. Nonetheless, even large errors in estimates of the distribution of genotype, genotype--phenotype associations, effectiveness and numbers of patients will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. Further research could help to clarify the many uncertainties that exist. However, although doing so will be of clinical interest, it is questionable whether, within the current pricing environment, such research would have any substantive impact on policy decisions. It is highly improbable that, whatever the findings of such research, the ICER could be brought down by the orders of magnitude required to make ERT an efficient use of health service resources. (The possible exception to this would be investigating the most efficient alternative treatment strategies for using ERT in a paediatric population only.) Moreover, if under equity considerations for orphan diseases the NHS feels it is important to provide this drug, regardless of its cost-effectiveness, then refining the precision of the ICER estimate also becomes superfluous.

A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness.

OBJECTIVES: This report reviews the clinical effectiveness and cost-effectiveness of adalimumab, etanercept and infliximab, agents that inhibit tumour necrosis factor-alpha (TNF-alpha), when used in the treatment of rheumatoid arthritis (RA) in adults. DATA SOURCES: Electronic databases were searched up to February 2005. REVIEW METHODS: Systematic reviews of the literature on effectiveness and cost-effectiveness were undertaken and industry submissions to the National Institute for Health and Clinical Excellence (NICE) were reviewed. Meta-analyses of effectiveness data were also undertaken for each agent. The Birmingham Rheumatoid Arthritis Model (BRAM), a simulation model, was further developed and used to produce an incremental cost-effectiveness analysis. RESULTS: Twenty-nine randomised controlled trials (RCTs), most of high quality, were included. The only head-to-head comparisons were against methotrexate. For patients with short disease duration (

Imatinib for the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumours: systematic review and economic evaluation.

OBJECTIVES: To assess the clinical and cost-effectiveness of imatinib in the treatment of unresectable and/or metastatic, KIT-positive, gastrointestinal stromal tumours (GISTs), relative to current standard treatments. DATA SOURCES: Electronic databases. REVIEW METHODS: As there were no randomised trials that have directly compared imatinib with the current standard treatment in patients with advanced GIST, this review included non-randomised controlled studies, cohort studies, and case series that reported effectiveness results of treatment with imatinib and/or other interventions in patients with advanced GIST. The effectiveness assessment was based on the comparison of results from imatinib trials and results from studies of historical control patients. Economic evaluation was mainly based on an assessment and modification (when judged necessary) of a model submitted by Novartis. RESULTS: Evidence from published uncontrolled trials involving 187 patients, and from abstracts reporting similar uncontrolled trials involving 1700 patients, indicates that approximately 50% of imatinib-treated individuals with advanced GIST experience a dramatic clinical response in terms of at least a 50% reduction in tumour mass. At present, although useful data are accumulating, it is not possible to predict which patients may respond in this way. Fifteen studies where possible GIST patients had been treated with therapies other than imatinib or best supportive care were also identified. All imatinib-treated patients experienced adverse effects, although they were relatively mild. Overall, imatinib was reported to be well tolerated. The most common serious events included unspecified haemorrhage and neutropenia. Skin rash, oedema and periorbital oedema were the common adverse events observed. Patients on the highest dose regimen (1000 mg per day in one trial) may experience dose-limiting drug toxicity. A structured assessment was carried out of the Novartis economic evaluation of imatinib for unresectable and/or metastatic GIST. The model was clearly presented and well written, its structure and input data were transparent, and the level of simplification was reasonable in terms of the objectives and data availability. However, the original Novartis model overestimated the cost-effectiveness of imatinib because of disproportion of survival and time-to-treatment failure in the imatinib arm, and the use of a possibly biased survival curve for patients in the control arm. The original Novartis model was modified to correct these two important shortcomings, which made it less sensitive to the choice of the survival curve for the control patients. According to the modified Novartis model, the estimated cost per quality-adjusted life-year (QALY) was 85,224 UK pounds (range 51,515--98,889 UK pounds) after 2 years, 41,219 UK pounds (27,331--44,236 UK pounds) after 5 years and 29,789 UK pounds (21,404--33,976 UK pounds) after 10 years. The results from a new Birmingham model were also within the range of estimates from the modified Novartis model. CONCLUSIONS: Evidence from uncontrolled studies indicates that the treatment with imatinib brings about clinically significant shrinkage of tumour mass in about half of patients with unresectable and/or metastatic, KIT-positive GIST. Results of modelling based on data from uncontrolled studies suggest that imatinib treatment improves survival in patients with unresectable and/or metastatic GIST. The economic evaluation modelling suggests that the cost per QALY gained ranges from 51,515 to 98,889 UK pounds after 2 years, from 27,331 to 44,236 UK pounds after 5 years, and from 21,404 to 33,976 UK pounds after 10 years. Further research is needed into quality of life within trials involving patients with advanced malignancy, and long-term follow-up of adverse events is needed. Subgroup analysis of which, if any, patient types have a better or worse response to imatinib is also required. Analysis of individual patient data may be a good way of exploring these issues. There are many uncertainties surrounding imatinib prescription, such as the length of time patients should be on imatinib, the dose, drug resistance and the optimum time-point in the disease course at which to give the drug. Secondary research such as an update of this systematic review and a reassessment of the model is highly recommended when ongoing trials reach completion.

Treatments for fatigue in multiple sclerosis: a rapid and systematic review.

BACKGROUND: Multiple sclerosis (MS) is an important problem both for people with the disease and for society. There is no cure, and alleviation of symptoms forms the cornerstone of care. Excessive fatigue that severely limits activity is experienced by at least two-thirds of the estimated 60,000 people with MS in the UK. OBJECTIVES: (1) To identify current treatments for fatigue in MS and their evidence-base. (2) To systematically review the evidence for those treatments that have been investigated in more than one rigorous study, in order to determine their effectiveness and cost-effectiveness. METHODS: The review was carried out in two stages: a formal scoping review (to assess the range of interventions used by people with MS), and a systematic review for treatments that had been identified as promising and that had been investigated in clinical trials (as identified in the scoping review). A systematic review of research on costs and cost-effectiveness of those interventions identified as promising was also performed. Electronic databases, including MEDLINE and EMBASE, were searched for the period 1991-June 1999 (scoping review) and 1966-December 1999 (systematic review). Reference lists from publications were also searched, and experts were contacted for any additional information not already identified. RESULTS: Interventions identified for the treatment of fatigue in MS (1) Behavioural advice. This is the main element of initial clinical management and no rigorous research of its effectiveness was identified. (2) Drugs (amantadine, pemoline, potassium-channel blockers and antidepressants). (3) Training, rehabilitation and devices (cooling vests and electromagnetic fields). (4) Alternative therapies (bee venom, cannabis, acupuncture/acupressure and yoga). Only two drugs, amantadine and pemoline, met the criteria for full systematic review. RESULTS - EFFECTIVENESS OF AMANTADINE: One parallel and three crossover trials were found, involving a total of 236 people with MS. All studies were open to bias. All studies showed a pattern in favour of amantadine compared with placebo, but there is considerable uncertainty about the validity and clinical significance of this finding. This pattern of benefit was considerably undermined when different assumptions were used in the sensitivity analysis. RESULTS - EFFECTIVENESS OF PEMOLINE: One parallel and one crossover trial were found involving a total of 126 people with MS. Both studies were open to bias. There was no overall tendency in favour of pemoline over placebo and an excess of reports of adverse effects with pemoline. RESULTS - HEALTH ECONOMIC ANALYSIS: The drug costs of amantadine and pemoline are modest (pound 200 and pound 80 per annum, respectively). No economic evaluations were identified in the systematic review, and available data were insufficient to allow modelling of cost-effectiveness in this rapid review. CONCLUSIONS: There is insufficient evidence to allow people with MS, clinicians or policy makers to make informed decisions on the appropriate use of the many treatments on offer. Only amantadine appears to have some proven ability to alleviate the fatigue in MS, though only a proportion of users will obtain benefit and then only some of these patients will benefit sufficiently to take the drug in the long term. CONCLUSIONS - RECOMMENDATIONS FOR RESEARCH: The frequency, severity and impact of fatigue, the poverty of available research, and the absence of any ongoing research, suggest that new research is an urgent priority. People with MS, clinicians and policy makers should work together to ensure that the evidence required is collected as quickly as possible by encouraging involvement in rigorous research. Research should not be restricted to the two drugs reviewed in depth in this report. All interventions identified in the scoping review (see above) should be considered, as should basic scientific research into the underlying mechanism of fatigue in MS.

Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.

OBJECTIVES: To determine the role of autoantibody tests for autoimmune diseases in children with newly diagnosed type 1 diabetes mellitus. DATA SOURCES: MEDLINE, EMBASE and the Cochrane Library. Citation lists of included studies were scanned and relevant professional and patient websites reviewed. Laboratories and manufacturers were contacted to identify ongoing or unpublished research. REVIEW METHODS: Following scoping searches on thyroid and coeliac autoantibodies, a systematic review of autoantibody tests for diagnosis of coeliac disease was carried out. Studies were included where cohorts of untreated patients with unknown disease status were included, all patients had undergone the reference test (biopsy) and antibody tests, and sensitivity and specificity were reported or calculable. Selected studies were then evaluated against a quality checklist. Summary statistics of diagnostic accuracy, i.e. sensitivity, specificity, positive and negative likelihood ratios and diagnostic odds ratios, were calculated for all studies. A decision analytic model was developed to evaluate the cost utility of screening for coeliac disease at diagnosis of diabetes. RESULTS: All antibody tests for diagnosis of coeliac disease showed reasonably good diagnostic test accuracy. Studies reported variable measures of test accuracy, which may be due to aspects of study quality, differences in the tests and their execution in the laboratories, different populations and reference standards. The decision analytic model indicated screening for coeliac disease at diagnosis of diabetes was cost-effective. Sensitivity analyses exploring variations in the cost and disutility of gluten-free diet, the utilities attached to treated and untreated coeliac disease and the decrease in life expectancy associated with treated and untreated coeliac disease did substantially affect the cost-effectiveness of the screening strategies considered. CONCLUSIONS: In terms of test accuracy in testing for coeliac disease, immunoglobulin A (IgA) anti-endomysium is the most accurate test. If an enzyme-linked immunoassay test was required, which may be more suitable for screening purposes as it can be semi-automated, testing for IgA tissue transglutaminase is likely to be most accurate. The decision analytic model shows that the most accurate tests combined with confirmatory biopsy are the most cost-effective, whilst combinations of tests add little or no further value. There is limited information regarding test accuracy in screening populations with diabetes, and there is some uncertainty over whether the test characteristics would remain the same. Further research is required regarding the role of screening in silent coeliac disease and regarding long-term outcomes and complications of untreated coeliac disease.

Screening for fragile X syndrome: a literature review and modelling study.

OBJECTIVES: To compare the effectiveness, estimate the associated costs, and summarise available evidence about the feasibility and acceptability of different screening strategies in England and Wales. Also to establish a model for estimating effectiveness and costs of these different strategies. DATA SOURCES: Literature searches were restricted to MEDLINE and EMBASE, as well as citations in included papers. A broad search strategy was used involving all aspects of fragile X syndrome (FXS) and covered all relevant literature published between 1991 and 2001. REVIEW METHODS: An assessment was conducted of published literature and efforts focused on the development of a model that could be used to synthesise data from various sources, estimate cost-effectiveness of different strategies, and conduct sensitivity analyses according to different assumptions. RESULTS: The identified screening programmes were effective in detecting carriers, but a comparison of different strategies was not possible. Simulation results by the FXS Model showed that, over the first 10 years, 4% of premutation (PM) females and 70% of full mutation (FM) females could be detected by active cascade screening; it is 10% and 58%, respectively, by prenatal screening. The maximal detection rate for FM carriers by active cascade screening is higher than that by prenatal screening (91% versus 71%). However, the maximal rate of detection of female PM carriers by active cascade screening (6%) is much lower than that by prenatal screening (60%). During the first 10 years of simulation, the estimated direct cost per year to the NHS in England and Wales is 0.7-0.2 million pounds sterling by active cascade screening and 14.5-9.1 million pounds sterling by a programme of prenatal screening. The incremental cost per extra carrier detected (using current practice as the reference standard) is on average only 165 pounds sterling by active cascade screening and 7543 pounds sterling by prenatal screening. The incremental cost per FXS birth avoided is on average 8494 pounds sterling by active cascade screening and 284,779 pounds sterling by prenatal screening. CONCLUSIONS: The empirical evidence suggests that both prenatal screening and cascade screening are feasible and acceptable. Population-based prenatal screening is more efficacious, but it will cost more than active cascade screening. The active cascade screening of affected families is more efficient, cheaper, but less effective than a population-based prenatal screening. It is suggested that both strategies be evaluated in large-scale trials, which might also help to determine whether and how the different strategies could be simultaneously or sequentially combined.

Identification and assessment of ongoing trials in health technology assessment reviews.

OBJECTIVES: To assess the importance of ongoing trials in health technology assessment reviews (HTARs) for the National Institute for Clinical Excellence and to provide practical recommendations for identifying ongoing trials and assessing their possible impact. DATA SOURCES: Electronic databases. REVIEW METHODS: Ongoing trials (or trials in progress) were defined as any trials that have started but where the results are not yet available or only interim results are available for HTARs. This methodological review included: (1) an assessment of ongoing trials in HTARs completed by the end of August 2002, (2) a survey and assessment of trial registers and other sources of ongoing trials and (3) a summary and assessment of available methods for assessing the possible impacts of ongoing trials. RESULTS: The identification of ongoing trials is a common phenomenon in reviews of health technology assessment. Twenty-three of the 32 HTARs identified one or more ongoing trials and in eight of these the information on identified ongoing trials was not considered in the evidence synthesis and research recommendations. All but one HTAR that considered the potential impact of ongoing trials adopted a narrative approach. Trial registers and grey literature are important sources of information on ongoing trials. All 32 HTARs explicitly or implicitly searched for unpublished studies, and/or ongoing trials and/or grey literature and trial registers. The assessment of six commonly used trial registers suggested that most registers provided sufficient information for reviewers to decide the relevance of identified ongoing trials. However, it is sometimes extremely difficult to know whether ongoing trials identified from different sources (registers) are the same trials or belong to the same multicentre trials. The ISRCTN (the International Standard Randomised Controlled Trial Number) is the most reliable system but it has not been widely adopted. The qualitative assessment of ongoing trials compared major features of completed and ongoing trials, providing information about the possible impact of ongoing trials in terms of relevance, validity, reliability and generalisability. Quantitative methods to assess the impact of ongoing trials include cumulative meta-analysis related methods, fail-safe N, Bayesian data monitoring, and Bayesian interim predictions. The most useful method may be the Bayesian predictive probability, which estimates predictive probabilities for any possible values of treatment effect. A case study indicated that the appropriate use of quantitative methods would strengthen findings from narrative assessment of possible impact of ongoing trials. CONCLUSIONS: Identification of ongoing trials is common in HTARs. Searching for ongoing trials in effectiveness reviews should be more thorough and explicit. Conversely, primary researchers, in particular those working with in multicentre trials, should label ongoing trials more clearly, preferably by ISRCTN. Qualitative assessment of identified ongoing trials is crucial and informative. Available quantitative methods could be used to strengthen findings from narrative assessment, although further research and more empirical examples are required. Information from ongoing trials may contribute to syntheses of results, conclusions and recommendations for future research. Future research is suggested into the identification and assessment of ongoing trials in other systematic reviews of effectiveness of health care interventions; existing and new methods for incorporating information on ongoing trials; comparing estimated impacts with the actual results of ongoing trials; and to incorporate findings from the assessment of ongoing trials into decision models.

Dual chamber versus single chamber ventricular pacemakers for sick sinus syndrome and atrioventricular block.

BACKGROUND: Dual chamber pacing or single chamber atrial pacing ('physiologic' pacing) is believed to have an advantage over single chamber ventricular pacing in that it resembles cardiac physiology more closely by maintaining atrioventricular (AV) synchrony and dominance of the sinus node, which in turn may reduce cardiovascular morbidity and mortality thus contributing to patient survival and quality of life. However, a significant proportion of pacemakers currently implanted are single chamber ventricular pacemakers. OBJECTIVES: The objective of this review was to assess the short- and long-term clinical effectiveness of dual chamber pacemakers compared to single chamber ventricular pacemakers in adults with AV block, sick sinus syndrome or both. An additional objective was to assess separately any potential differences in effectiveness between dual chamber pacing and single chamber atrial pacing. The clinical effectiveness of single chamber atrial pacing versus single chamber ventricular pacing was not examined. SEARCH STRATEGY: The Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2002), MEDLINE (1966 to 2002), EMBASE (1980 to 2002) and the Science Citation Index (1980 to 2002) were searched on 19th August 2002. Citation lists and web sites were checked and researchers in the field contacted. SELECTION CRITERIA: Parallel group or crossover randomised controlled trials of at least 48 hours duration comparing dual chamber pacing and single chamber ventricular pacing, and investigating cardiovascular morbidity, mortality, patient related quality of life, exercise capacity and complication rates. DATA COLLECTION AND ANALYSIS: Data was extracted onto pre-piloted data extraction forms. Quality assessment was undertaken using a checklist, with a sub-sample of quality data independently extracted by a second reviewer. Where appropriate data was available, meta-analysis was performed. Where meta-analysis was not possible, the number of studies showing a positive, neutral or negative direction of effect and statistical significance were simply counted. MAIN RESULTS: Five parallel and 26 crossover randomised controlled trials were identified. The quality of reporting was found to be poor. Pooled data from parallel studies shows a statistically non-significant preference for physiologic pacing (primarily dual chamber pacing) for the prevention of stroke, heart failure and mortality, and a statistically significant beneficial effect regarding the prevention of atrial fibrillation (odds ratio (OR) 0.79, 95% CI 0.68 to 0.93). Both parallel and crossover studies favour dual chamber pacing with regard to pacemaker syndrome (parallel: Peto OR 0.11, 95% CI 0.08 to 0.14; crossover: standardised mean difference (SMD) -0.74, 95% CI - 0.95 to -0.52). Pooled data from crossover studies shows a statistically significant trend towards dual chamber pacing being more favourable in terms of exercise capacity (SMD -0.24, 95% CI -0.03 to -0.45). No individual studies reported a significantly more favourable outcome with single chamber ventricular pacing. REVIEWERS' CONCLUSIONS: This review shows a trend towards greater effectiveness with dual chamber pacing compared to single chamber ventricular pacing, which supports the current British Pacing and Electrophysiology Group's Guidelines regarding atrioventricular block. Additional randomised controlled trial evidence from ongoing trials in this area will further inform the debate.

The effectiveness of routine dental checks: a systematic review of the evidence base.

AIMS: To systematically review the effectiveness of routine dental checks of different recall frequencies in adults and children. METHODS: Search methods included electronic bibliographic databases up to March 2001, relevant internet sites, citation checking and contact with experts and professional dental bodies. INCLUSION CRITERIA: (1) STUDY DESIGN: any; (2) POPULATION: deciduous, mixed and permanent dentition; (3) INTERVENTION: 'Routine dental check': 'clinical examination, advice, charting (including monitoring of periodontal status) and report' as defined in the NHS Executive General Dental Service Statement of Dental Remuneration; (4) Comparator: no routine dental check or routine dental check(s) of different recall frequency; (5) PRIMARY OUTCOMES: caries, periodontal disease, quality of life, oral cancer. RESULTS: Twenty eight studies were identified for the review. Studies were poorly reported and clinically heterogenous which restricted comparison between studies and limited generalisability to the UK situation. There was no consistency across multiple studies in the direction of effect of different dental check frequencies on measures of caries in deciduous mixed or permanent dentition, periodontal disease or oral cancer in permanent dentition. No studies were identified linking empirical measures of quality of life associated with oral health and dental check frequency. CONCLUSIONS: There is no existing high quality evidence to support or refute the practice of encouraging six-monthly dental checks in adults and children.

Combined anticoagulation and antiplatelet therapy for high-risk patients with atrial fibrillation: a systematic review.

BACKGROUND: Previous research suggests uncertainty whether or not there is any additional benefit in adding antiplatelet therapy (APT) to anticoagulation therapy (ACT) in patients with high-risk atrial fibrillation (AF) in terms of reduction in vascular events, including stroke. The existing guidelines acknowledge an increased risk of bleeding associated with such a strategy; however, there is no consensus on the treatment pathway. OBJECTIVES: To determine, by undertaking a systematic review, if the addition of APT to ACT is beneficial compared with ACT alone in patients with AF who are considered to be at high risk of thromboembolic events (TEs). DATA SOURCES: Data sources included bibliographic databases {the Cochrane Library [Cochrane Central Register of Controlled Trials (CENTRAL)], MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, ClinicalTrials.gov, National Institute for Health Research (NIHR) Clinical Research Network Portfolio, Current Controlled Trials (CCT) and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP)}, reference lists from identified systematic reviews and relevant studies, and contact with clinical experts. Searches were from inception to September 2010 and did not use language restrictions or study design filters. REVIEW METHODS: Studies of any design were included to evaluate clinical effectiveness, including randomised controlled trials (RCTs), non-randomised comparisons, cohort studies, case series or registries, longitudinal studies, systematic reviews and meta-analyses, and conference abstracts published after 2008. Inclusion criteria consisted of a population with AF, at high-risk of TEs, aged ≥ 18 years, on combined ACT and APT compared with others on ACT alone or ACT plus placebo. Inclusion decisions, assessment of study quality and data extraction were undertaken using methods to minimise bias. RESULTS: Fifty-three publications were included, reporting five RCTs (11 publications), 18 non-randomised comparisons (24 publications) and 18 publications that reported reviews, which added no further data. There was variation in the population, types and doses of ACT and APT, definitions of outcomes, and length of follow-up between the studies. There was a paucity of directly randomised high-quality RCTs, whereas non-randomised comparisons were found to have significant confounding factors. No studies looked at the effect of ACT plus APT compared with ACT alone on vascular events in patients with AF following acute coronary syndrome (ACS) or percutaneous coronary intervention. In most studies, significant differences in event rates were not seen between the patients on combined therapy compared with those on ACT alone for outcomes such as stroke (including haemorrhagic and ischaemic strokes), rates of transient ischaemic attacks, composite end points of stroke and systemic embolism (SE), SE alone, acute myocardial infarction, mortality (vascular or all cause) or bleeding events. There was conflicting evidence regarding rates of major adverse events consisting of composite end points, although event rates were generally low. LIMITATIONS: An attempt was made to identify all of the available evidence around the subject despite the dearth of directly randomised studies using a robust review methodology. There was a paucity of directly randomised evidence to undertake a meta-analysis for the merits of one technology over another. The selection criteria were kept necessarily broad with regard to the population, intervention and comparator in order to capture all relevant studies. CONCLUSIONS: This systematic review suggests that there is still insufficient evidence to advocate a clear benefit of the addition of APT to ACT compared with ACT alone in reducing the risk of vascular events in a population of patients at high risk of TEs resulting from AF. It is recommended that a definitive prospective RCT needs to be undertaken in a population at high risk of atherosclerotic coronary artery and other vascular events in addition to being at high risk of AF-mediated TEs. From the UK context, at the time of writing, any future trial should compare adjusted-dose warfarin [international normalised ratio (INR) 2.0-3.0] plus aspirin (75-325 mg) with adjusted-dose warfarin (INR 2.0-3.0). However, given the emergence of newer anticoagulation agents (dabigatran, rivaroxaban and apixaban) this prioritisation may need to be revisited in the future to reflect current best clinical practice. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

A systematic review and economic evaluation of subcutaneous and sublingual allergen immunotherapy in adults and children with seasonal allergic rhinitis.

BACKGROUND: Severe allergic rhinitis uncontrolled by conventional medication can substantially affect quality of life. Immunotherapy involves administering increasing doses of a specific allergen, with the aim of reducing sensitivity and symptomatic reactions. Recent meta-analyses have concluded that both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are more effective than placebo in reducing symptoms. It is uncertain which route of administration is more effective and whether or not treatment is cost-effective. OBJECTIVE: To determine the comparative clinical effectiveness and cost-effectiveness of SCIT and SLIT for seasonal allergic rhinitis in adults and children. DATA SOURCES: Electronic databases {MEDLINE, EMBASE, The Cochrane Library [Cochrane Central Register of Controlled Trials (CENTRAL)], NHS Economic Evaluation Database (NHS EED)} and trial registries (from inception up to April 2011). REVIEW METHODS: Standard systematic review methods were used for study selection, data extraction and quality assessment. Double-blind randomised, placebo-controlled trials of SCIT or SLIT, or of SCIT compared with SLIT, and economic evaluations were included. Meta-analysis and indirect comparison meta-analysis and meta-regression were carried out. A new economic model was constructed to estimate cost-utility. RESULTS: Meta-analyses found statistically significant effects for SCIT and SLIT compared with placebo across a number of outcome measures and for the vast majority of subgroup analyses (type and amount of allergen, duration of treatment). There was less evidence for children, but some results in favour of SLIT were statistically significant. Indirect comparisons did not provide conclusive results in favour of either SCIT or SLIT. Economic modelling suggested that, when compared with symptomatic treatment (ST), both SCIT and SLIT may become cost-effective at a threshold of £20,000-30,000 per quality-adjusted life-year (QALY) from around 6 years, or 5 years for SCIT compared with SLIT (NHS and patient perspective). LIMITATIONS: It is uncertain to what extent changes in the outcome measures used in the trials translate into clinically meaningful benefits. Cost-effectiveness estimates are based on a simple model, limited data and a number of assumptions, and should be seen as indicative only. CONCLUSIONS: A benefit from both SCIT and SLIT compared with placebo has been consistently demonstrated, but the extent of this effectiveness in terms of clinical benefit is unclear. Both SCIT and SLIT may be cost-effective compared with ST from around 6 years (threshold of £20,000-30,000 per QALY). Further research is needed to establish the comparative effectiveness of SCIT compared with SLIT and to provide more robust cost-effectiveness estimates. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Effectiveness and cost-effectiveness of computer and other electronic aids for smoking cessation: a systematic review and network meta-analysis.

BACKGROUND: Smoking is harmful to health. On average, lifelong smokers lose 10 years of life, and about half of all lifelong smokers have their lives shortened by smoking. Stopping smoking reverses or prevents many of these harms. However, cessation services in the NHS achieve variable success rates with smokers who want to quit. Approaches to behaviour change can be supplemented with electronic aids, and this may significantly increase quit rates and prevent a proportion of cases that relapse. OBJECTIVE: The primary research question we sought to answer was: What is the effectiveness and cost-effectiveness of internet, pc and other electronic aids to help people stop smoking? We addressed the following three questions: (1) What is the effectiveness of internet sites, computer programs, mobile telephone text messages and other electronic aids for smoking cessation and/or reducing relapse? (2) What is the cost-effectiveness of incorporating internet sites, computer programs, mobile telephone text messages and other electronic aids into current nhs smoking cessation programmes? and (3) What are the current gaps in research into the effectiveness of internet sites, computer programs, mobile telephone text messages and other electronic aids to help people stop smoking? DATA SOURCES: For the effectiveness review, relevant primary studies were sought from The Cochrane Library [Cochrane Central Register of Controlled Trials (CENTRAL)] 2009, Issue 4, and MEDLINE (Ovid), EMBASE (Ovid), PsycINFO (Ovid), Health Management Information Consortium (HMIC) (Ovid) and Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCOhost) from 1980 to December 2009. In addition, NHS Economic Evaluation Database (NHS EED) and Database of Abstracts of Reviews of Effects (DARE) were searched for information on cost-effectiveness and modelling for the same period. Reference lists of included studies and of relevant systematic reviews were examined to identify further potentially relevant studies. Research registries of ongoing studies including National Institute for Health Research (NIHR) Clinical Research Network Portfolio Database, Current Controlled Trials and ClinicalTrials.gov were also searched, and further information was sought from contacts with experts. REVIEW METHODS: Randomised controlled trials (RCTs) and quasi-RCTs evaluating smoking cessation programmes that utilise computer, internet, mobile telephone or other electronic aids in adult smokers were included in the effectiveness review. Relevant studies of other design were included in the cost-effectiveness review and supplementary review. Pair-wise meta-analyses using both random- and fixed-effects models were carried out. Bayesian mixed-treatment comparisons (MTCs) were also performed. A de novo decision-analytical model was constructed for estimating the cost-effectiveness of interventions. Expected value of perfect information (EVPI) was calculated. Narrative synthesis of key themes and issues that may influence the acceptability and usability of electronic aids was provided in the supplementary review. RESULTS: This effectiveness review included 60 RCTs/quasi-RCTs reported in 77 publications. Pooled estimate for prolonged abstinence [relative risk (RR) = 1.32, 95% confidence interval (CI) 1.21 to 1.45] and point prevalence abstinence (RR = 1.14, 95% CI 1.07 to 1.22) suggested that computer and other electronic aids increase the likelihood of cessation compared with no intervention or generic self-help materials. There was no significant difference in effect sizes between aid to cessation studies (which provide support to smokers who are ready to quit) and cessation induction studies (which attempt to encourage a cessation attempt in smokers who are not yet ready to quit). Results from MTC also showed small but significant intervention effect (time to relapse, mean hazard ratio 0.87, 95% credible interval 0.83 to 0.92). Cost-threshold analyses indicated some form of electronic intervention is likely to be cost-effective when added to non-electronic behavioural support, but there is substantial uncertainty with regard to what the most effective (thus most cost-effective) type of electronic intervention is, which warrants further research. EVPI calculations suggested the upper limit for the benefit of this research is around £ 2000-3000 per person. LIMITATIONS: The review focuses on smoking cessation programmes in the adult population, but does not cover smoking cessation in adolescents. Most available evidence relates to interventions with a single tailored component, while evidence for different modes of delivery (e.g. e-mail, text messaging) is limited. Therefore, the findings of lack of sufficient evidence for proving or refuting effectiveness should not be regarded as evidence of ineffectiveness. We have examined only a small number of factors that could potentially influence the effectiveness of the interventions. A comprehensive evaluation of potential effect modifiers at study level in a systematic review of complex interventions remains challenging. Information presented in published papers is often insufficient to allow accurate coding of each intervention or comparator. A limitation of the cost-effectiveness analysis, shared with several previous cost-effectiveness analyses of smoking cessation interventions, is that intervention benefit is restricted to the first quit attempt. Exploring the impact of interventions on subsequent attempts requires more detailed information on patient event histories than is available from current evidence. CONCLUSIONS: Our effectiveness review concluded that computer and other electronic aids increase the likelihood of cessation compared with no intervention or generic self-help materials, but the effect is small. The effectiveness does not appear to vary with respect to mode of delivery and concurrent non-electronic co-interventions. Our cost-effectiveness review suggests that making some form of electronic support available to smokers actively seeking to quit is highly likely to be cost-effective. This is true whether the electronic intervention is delivered alongside brief advice or more intensive counselling. The key source of uncertainty is that around the comparative effectiveness of different types of electronic interventions. Our review suggests that further research is needed on the relative benefits of different forms of delivery for electronic aids, the content of delivery, and the acceptability of these technologies for smoking cessation with subpopulations of smokers, particularly disadvantaged groups. More evidence is also required on the relationship between involving users in the design of interventions and the impact this has on effectiveness, and finally on how electronic aids developed and tested in research settings are applied in routine practice and in the community.

A systematic review and economic evaluation of the use of tumour necrosis factor-alpha (TNF-α) inhibitors, adalimumab and infliximab, for Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a severe, lifelong disease characterised by inflammation of the gastrointestinal mucosa. The impact on patients and society is high as ill health can be lifelong and can negatively affect patients' quality of life. Costs to the NHS are high, particularly for patients needing hospitalisation. Conventional treatment pathways are complex. More recently, a group of drugs called tumour necrosis factor (TNF) inhibitors (anti-TNF-α agents) have been evaluated for their effectiveness in CD. One of these, infliximab, is currently recommended by the National Institute for Health and Clinical Excellence (NICE; 2002) for patients with severe, active CD where patients are refractory to or intolerant of conventional treatment. OBJECTIVES: To investigate whether there is evidence for greater clinical effectiveness or cost-effectiveness for either adalimumab or infliximab. DATA SOURCES: Cochrane Library (Cochrane Central Register of Controlled Trials) 2007 Issue 2; MEDLINE (Ovid) 2000 to May/June 2007; MEDLINE In-Process & Other Non-Indexed Citations (Ovid) 4 June and 26 June 2007; EMBASE (Ovid) 2000 to May/June 2007. The European Medicines Agency, the US Food and Drug Administration and other relevant websites. REVIEW METHODS: Standard systematic review methods were used for study identification and selection, data extraction and quality assessment. Only randomised controlled trials (RCTs) comparing adalimumab or infliximab with standard treatment (placebo), RCTs comparing adalimumab with infliximab, or RCTs comparing different dosing regimens of either adalimumab or infliximab in adults and children with moderate-to-severe active CD intolerant or resistant to conventional treatment were eligible for inclusion. A systematic review of published studies on the cost and cost-effectiveness of adalimumab and infliximab was undertaken. The economic models of cost-effectiveness submitted by the manufacturers of both drugs were critically appraised and, where appropriate, rerun using parameter inputs based on the evidence identified by the authors of the technology asessment report. A de novo Markov state transition model was constructed to calculate the incremental cost-effectiveness ratio for adalimumab and infliximab therapy compared with standard care. RESULTS: Based on 11 trials, there was evidence from both induction and maintenance trials that both adalimumab and infliximab therapy were beneficial compared with placebo (standard care) for adults with moderate-to-severe CD and, for infliximab, for adults with fistulising CD; results were statistically significant for some time points. Between 6% and 24% (adalimumab), and 21% and 44% (infliximab) more patients achieved remission with anti-TNF-α antibodies than with placebo in the induction trials. Between 24% and 29% (adalimumab), and 14% and 24% (infliximab) more patients achieved remission with anti-TNF-α antibodies in the two large maintenance trials at reported follow-up. In fistulising CD, between 29% and 42% (induction trial) and 23% (maintenance trial) more patients achieved a > 50% reduction in fistulas with infliximab than with placebo at reported follow-up. There was no direct evidence to show that 'responders' were more likely to benefit from treatment than 'non-responders' in the longer term. Few differences were found between treatment and standard care arms for selected adverse events, though high proportions of scheduled crossovers resulted in a lack of a true placebo group in most of the maintenance trials. No published studies on the cost-effectiveness of adalimumab were identified. The four independently funded studies identified for infliximab suggested high cost-effectiveness ratios [all above £50,000/quality-adjusted life-year (QALY) for non-fistulising disease and all above £100,000/QALY for fistulising disease]. A budget impact assessment suggested that total cost to the NHS in England and Wales for induction in severe disease only could range between £17M and £92M and for maintenance for 1 year between £140M and £200M. LIMITATIONS: Regarding clinical effectiveness, there were concerns about the trial design and lack of clarity, which may have affected interpretation of results. None of the trials matched exactly the licence indications or NICE guidance, which specify the use of these drugs in patients with 'severe' disease. All trials were multicentre, and applicability to UK populations, particularly in terms of standard care being provided and in terms of patients having failed or having become intolerant to conventional treatment, was uncertain. The published economic models relied heavily on little information and data from small samples. CONCLUSIONS: Anti-TNF therapy with adalimumab or infliximab may have a beneficial effect compared with standard care on outcome measures for induction and maintenance. The findings were that for induction, both adalimumab and infliximab are cost-effective (dominant relative to standard care) in the management of severe CD, and adalimumab (but not infliximab) is cost-effective for moderate CD, according to limits generally accepted by NICE. On the basis of the analysis presented here, neither drug is likely to be cost-effective as maintenance therapy for moderate or severe disease. Perhaps, most importantly, the analysis reflected the fact that a substantial number of patients would achieve remission under standard care and that the incidence of relapse among those in remission was such that maintenance therapy would have to show greater effectiveness than at present and/or be much less costly than it currently is in order to reach the levels of generally accepted cost-effectiveness. Any future trials need to be designed to meet the particular challenges of measuring and quantifying benefit in this patient group. FUNDING: The research was funded by the HTA programme on behalf of NICE.

Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a tumour necrosis factor inhibitor: a systematic review and economic evaluation.

BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory condition that typically causes a symmetrical chronic arthritis. Timely use of disease-modifying antirheumatic drugs (DMARDs) is an essential aspect of disease management, but many patients may not respond even when conventional agents are used optimally. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of adalimumab (ADA), etanercept (ETN), infliximab (IFX), rituximab (RTX) and abatacept (ABT) when used in patients with RA who have tried conventional agents and have failed to improve after trying a first tumour necrosis factor (TNF) inhibitor. DATA SOURCES: A systematic review of primary studies was undertaken. Databases searched included the Cochrane Library, MEDLINE (Ovid) and EMBASE up to July 2009. STUDY SELECTION: Two reviewers assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. STUDY APPRAISAL: Data from included studies were extracted by one reviewer and checked by a second. The quality of included studies was assessed independently by two reviewers, with any disagreements resolved by discussion and consultation with a third reviewer if necessary. RESULTS: Thirty-five studies were included in the systematic review: five randomised controlled trials (RCTs), one comparative study, one controlled study and 28 uncontrolled studies. One RCT (REFLEX) demonstrated the effectiveness of RTX. At 6 months significantly more patients treated with RTX achieved American College of Rheumatology (ACR) 20 [relative risk (RR) = 2.85, 95% confidence interval (CI) 2.08 to 3.91] and ACR70 (RR = 12.14, 95% CI 2.96 to 49.86) compared with those treated with the placebo. Differences between groups in favour of RTX were observed at 6 months for mean change from baseline in Disease Activity Score 28 (DAS28) (mean difference -1.50, 95% CI -1.74 to -1.26) and mean change from baseline in Health Assessment Questionnaire (HAQ) score (mean difference -0.30, 95% CI -0.40 to -0.20). One RCT (ATTAIN) demonstrated the effectiveness of ABT. At 6 months significantly more patients treated with ABT achieved ACR20 (RR = 2.56, 95% CI 1.77 to 3.69) and ACR70 (RR = 6.70, 95% CI 1.62 to 27.80) compared with those treated with placebo. Significant differences between groups in favour of ABT were observed at 6 months for mean change from baseline in DAS28 score (mean difference -1.27, 95% CI -1.62 to -0.93) and mean change from baseline in HAQ score (mean difference -0.34). Twenty-eight uncontrolled studies observed improvement of effectiveness compared with before switching, in patients who switched to ADA, ETN or IFX after discontinued previous TNF inhibitor(s). Four studies were included in the systematic review of cost-effectiveness. Independent economic evaluation undertaken by the assessment group showed that compared with DMARDs, the incremental cost-effectiveness ratios (ICERs) were £34,300 [per quality-adjusted life-year (QALY)] for ADA, £38,800 for ETN, £36,200 for IFX, £21,200 for RTX and £38,600 for ABT. RTX dominates the TNF inhibitors and the ICER for ABT compared with RTX is over £100,000 (per QALY). LIMITATIONS: Paucity of evidence from RCTs for assessing the clinical effectiveness of TNF inhibitors and an absence of head-to-head trials comparing the five technologies. CONCLUSIONS: Evidence from RCTs suggests that RTX and ABT are more effective than supportive care. Data from observational studies suggest that the use of an alternative TNF inhibitor in patients who exhibit an inadequate response to a first TNF inhibitor may offer some benefit, but there remain uncertainties with regard to the magnitude of treatment effects and their cost-effectiveness. Future research should include head-to-head trials comparing the clinical effectiveness and cost-effectiveness of the technologies against each other and emerging biologics. FUNDING: This study was funded by the Health Technology Assessment programme of the National Institute for Health Research.

Imatinib as adjuvant treatment following resection of KIT-positive gastrointestinal stromal tumours.

This is a summary of the evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of adjuvant imatinib post resection of KIT-positive gastrointestinal stromal tumours (GISTs) compared with resection only in patients at significant risk of relapse. The ERG report is based on the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The bulk of the clinical evidence submitted was in the form of one randomised controlled trial (RCT), the Z9001 trial, funded by the manufacturer, which compared resection + adjuvant imatinib for 1 year to resection only. Results were immature, with median recurrence-free survival (RFS) not yet having been reached at the time of analysis. The trial did provide evidence of a delay in disease recurrence [1-year RFS rate of 98% in the imatinib arm vs 83% in the placebo arm [hazard ratio (HR) 0.35, 95% confidence interval (CI) 0.22 to 0.53, p < 0.0001)] but no evidence of an overall survival benefit. There was no long-term evidence around the rate of imatinib resistance over time with different treatment strategies (± adjuvant treatment). The relevant patient group for this appraisal is those at significant risk of relapse. These form a subgroup of the Z9001 trial, and all information regarding this group was designated 'Commercial-in-Confidence' (CIC). Median observation time for RFS was also CIC. The manufacturer constructed a Markov model comprising 10 health states designed to estimate costs and effects of treatment over a lifetime time horizon. The manufacturer's estimate of the base-case incremental cost-effectiveness ratio (ICER) was 22,937 pounds/quality-adjusted life-year (subsequently amended by the manufacturer to 23,601 pounds). While the structure of the model reasonably reflected the natural history of the disease, the ERG had numerous concerns regarding the selection of, and assumptions around, input parameters (utilities, monthly probabilities of recurrence and death). Furthermore, the model was set up in such a way that any delay in recurrence translated directly into a survival benefit, an assumption that has no evidence base. A further assumption not supported by evidence was that any treatment benefit gained in the first year is carried on for a further 2 years at the same rate. Appropriate probabilistic sensitivity analysis was undertaken on the base case only, but not on scenario analyses, or choice of model used to estimate long-term survival data. The model was not amenable to changes in input values, thus limiting any additional analyses by the ERG to test assumptions. Due to the large number of uncertainties and assumptions, the estimated ICERs should be regarded as highly uncertain. The guidance issued by NICE in June 2010 as a result of the STA does not recommend imatinib as adjuvant treatment after resection of gastrointestinal stromal tumours, although individuals currently receiving adjuvant imatinib should have the option to continue treatment until they and their clinician consider it appropriate to stop.

Infliximab for the treatment of acute exacerbations of ulcerative colitis.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of infliximab for the treatment of acute exacerbations of ulcerative colitis, in accordance with the licensed indication, based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence included four randomised controlled trials (RCTs), two comparing infliximab with placebo in patients not responsive to initial treatment with intravenous corticosteroids and one comparing ciclosporin with placebo. A fourth RCT compared ciclosporin with intravenous corticosteroids as the initial treatment after hospitalisation. The manufacturer's submission concluded that infliximab provides clinical benefit to patients with acute severe, steroid-refractory ulcerative colitis and is well tolerated; it also provides additional clinical benefits over ciclosporin, particularly avoidance of colectomy. A decision tree model was built to compare infliximab with strategies involving ciclosporin, standard care and surgery. After correcting a small number of errors in the model, the revised base-case incremental cost-effectiveness ratio (ICER) for infliximab compared with standard care was 20,000 pounds. However, sensitivity analyses revealed considerable uncertainty emanating from the weight of the patient, the timeframe considered and, most importantly, the colectomy rates used. When a more appropriate mix of trials were included in the estimation of colectomy rates, the ICER for infliximab rose to 48,000 pounds. The guidance issued by NICE on 31 October 2008 states that infliximab is recommended as an option for the treatment of acute exacerbations of severely active ulcerative colitis only in patients in whom ciclosporin is contraindicated or clinically inappropriate, based on a careful assessment of the risks and benefits of treatment in the individual patient; for people who do not meet this criterion, infliximab should only be used for the treatment of acute exacerbations of severely active ulcerative colitis in clinical trials.