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Background: To reduce expenditure on, and wastage of, drugs, some commissioners have encouraged general practitioners to issue shorter prescriptions, typically 28 days in length; however, the evidence base for this recommendation is uncertain., Objective: To evaluate the evidence of the clinical effectiveness and cost-effectiveness of shorter versus longer prescriptions for people with stable chronic conditions treated in primary care., Design/data Sources: The design of the study comprised three elements. First, a systematic review comparing 28-day prescriptions with longer prescriptions in patients with chronic conditions treated in primary care, evaluating any relevant clinical outcomes, adherence to treatment, costs and cost-effectiveness. Databases searched included MEDLINE (PubMed), EMBASE, Cumulative Index to Nursing and Allied Health Literature, Web of Science and Cochrane Central Register of Controlled Trials. Searches were from database inception to October 2015 (updated search to June 2016 in PubMed). Second, a cost analysis of medication wastage associated with < 60-day and ≥ 60-day prescriptions for five patient cohorts over an 11-year period from the Clinical Practice Research Datalink. Third, a decision model adapting three existing models to predict costs and effects of differing adherence levels associated with 28-day versus 3-month prescriptions in three clinical scenarios., Review Methods: In the systematic review, from 15,257 unique citations, 54 full-text papers were reviewed and 16 studies were included, five of which were abstracts and one of which was an extended conference abstract. None was a randomised controlled trial: 11 were retrospective cohort studies, three were cross-sectional surveys and two were cost studies. No information on health outcomes was available., Results: An exploratory meta-analysis based on six retrospective cohort studies suggested that lower adherence was associated with 28-day prescriptions (standardised mean difference -0.45, 95% confidence interval -0.65 to -0.26). The cost analysis showed that a statistically significant increase in medication waste was associated with longer prescription lengths. However, when accounting for dispensing fees and prescriber time, longer prescriptions were found to be cost saving compared with shorter prescriptions. Prescriber time was the largest component of the calculated cost savings to the NHS. The decision modelling suggested that, in all three clinical scenarios, longer prescription lengths were associated with lower costs and higher quality-adjusted life-years., Limitations: The available evidence was found to be at a moderate to serious risk of bias. All of the studies were conducted in the USA, which was a cause for concern in terms of generalisability to the UK. No evidence of the direct impact of prescription length on health outcomes was found. The cost study could investigate prescriptions issued only; it could not assess patient adherence to those prescriptions. Additionally, the cost study was based on products issued only and did not account for underlying patient diagnoses. A lack of good-quality evidence affected our decision modelling strategy., Conclusions: Although the quality of the evidence was poor, this study found that longer prescriptions may be less costly overall, and may be associated with better adherence than 28-day prescriptions in patients with chronic conditions being treated in primary care., Future Work: There is a need to more reliably evaluate the impact of differing prescription lengths on adherence, on patient health outcomes and on total costs to the NHS. The priority should be to identify patients with particular conditions or characteristics who should receive shorter or longer prescriptions. To determine the need for any further research, an expected value of perfect information analysis should be performed., Study Registration: This study is registered as PROSPERO CRD42015027042., Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Writing therapy to improve physical or mental health can take many forms. The most researched model of therapeutic writing (TW) is unfacilitated, individual expressive writing (written emotional disclosure). Facilitated writing activities are less widely researched., Data Sources: Databases, including MEDLINE, EMBASE, PsycINFO, Linguistics and Language Behaviour Abstracts, Allied and Complementary Medicine Database and Cumulative Index to Nursing and Allied Health Literature, were searched from inception to March 2013 (updated January 2015)., Review Methods: Four TW practitioners provided expert advice. Study procedures were conducted by one reviewer and checked by a second. Randomised controlled trials (RCTs) and non-randomised comparative studies were included. Quality was appraised using the Cochrane risk-of-bias tool. Unfacilitated and facilitated TW studies were analysed separately under International Classification of Diseases, Tenth Revision chapter headings. Meta-analyses were performed where possible using RevMan version 5.2.6 (RevMan 2012, The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark). Costs were estimated from a UK NHS perspective and three cost-consequence case studies were prepared. Realist synthesis followed Realist and Meta-narrative Evidence Synthesis: Evolving Standards guidelines., Objectives: To review the clinical effectiveness and cost-effectiveness of TW for people with long-term conditions (LTCs) compared with no writing, or other controls, reporting any relevant clinical outcomes. To conduct a realist synthesis to understand how TW might work, and for whom., Results: From 14,658 unique citations, 284 full-text papers were reviewed and 64 studies (59 RCTs) were included in the final effectiveness reviews. Five studies examined facilitated TW; these were extremely heterogeneous with unclear or high risk of bias but suggested that facilitated TW interventions may be beneficial in individual LTCs. Unfacilitated expressive writing was examined in 59 studies of variable or unreported quality. Overall, there was very little or no evidence of any benefit reported in the following conditions (number of studies): human immunodeficiency virus (six); breast cancer (eight); gynaecological and genitourinary cancers (five); mental health (five); asthma (four); psoriasis (three); and chronic pain (four). In inflammatory arthropathies (six) there was a reduction in disease severity [n = 191, standardised mean difference (SMD) -0.61, 95% confidence interval (CI) -0.96 to -0.26] in the short term on meta-analysis of four studies. For all other LTCs there were either no data, or sparse data with no or inconsistent, evidence of benefit. Meta-analyses conducted across all of the LTCs provided no evidence that unfacilitated emotional writing had any effect on depression at short- (n = 1563, SMD -0.06, 95% CI -0.29 to 0.17, substantial heterogeneity) or long-term (n = 778, SMD -0.04 95% CI -0.18 to 0.10, little heterogeneity) follow-up, or on anxiety, physiological or biomarker-based outcomes. One study reported costs, no studies reported cost-effectiveness and 12 studies reported resource use; and meta-analysis suggested reduced medication use but no impact on health centre visits. Estimated costs of intervention were low, but there was insufficient evidence to judge cost-effectiveness. Realist synthesis findings suggested that facilitated TW is a complex intervention and group interaction contributes to the perception of benefit. It was unclear from the available data who might benefit most from facilitated TW., Limitation: Difficulties with developing realist synthesis programme theory meant that mechanisms operating during TW remain obscure., Conclusions: Overall, there is little evidence to support the therapeutic effectiveness or cost-effectiveness of unfacilitated expressive writing interventions in people with LTCs. Further research focused on facilitated TW in people with LTCs could be informative., Study Registration: This study is registered as PROSPERO CRD42012003343., Funding: The National Institute for Health Research Health Technology Assessment programme.

Background: Vulval cancer causes 3-5% of all gynaecological malignancies and requires surgical removal and inguinofemoral lymphadenectomy (IFL). Complications affect > 50% of patients, including groin wound infection, lymphoedema and cellulitis. A sentinel lymph node (SLN) is the first groin node with the highest probability of malignancy. SLN biopsy would be useful if it could accurately identify patients in whom cancer has spread to the groin, without removing all groin nodes. SLNs can be identified by isosulfan blue dye and/or technetium-99 ((99m)Tc) radioactive tracer during lymphoscintigraphy. The blue dye/(99m)Tc procedure only detects SLN, not metastases - this requires histological examination, which can include ultrastaging and staining with conventional haematoxylin and eosin (H&E) or immunohistochemistry., Objectives: To determine the test accuracy and cost-effectiveness of the SLN biopsy with (99m)Tc and/or blue dye compared with IFL or clinical follow-up for test negatives in vulval cancer, through systematic reviews and economic evaluation., Data Sources: Standard medical databases, including MEDLINE, EMBASE, Science Citation Index and The Cochrane Library, medical search gateways, reference lists of review articles and included studies were searched to January 2011., Methods: For accuracy and effectiveness, standard methods were used and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Searches were to January 2011, with no language restrictions. Meta-analyses were carried out with Meta-Disc version 1.4 (Javier Zamora, Madrid, Spain) for accuracy; none was appropriate for effectiveness. The economic evaluation from a NHS perspective used a decision-tree model in DATA TreeAge Pro Healthcare 2001 (TreeAge Software, Inc., Williamstown, MA, USA). Six options (blue dye with H&E, blue dye with ultrastaging, (99m)Tc with H&E, (99m)Tc with ultrastaging, blue dye/(99m)Tc with H&E, blue dye/(99m)Tc with ultrastaging) were compared with IFL. Deterministic and probabilistic sensitivity analyses were conducted., Results: For accuracy, of the 26 included studies, most evaluated (99m)Tc/blue dye combined. Four studies had clinical follow-up only for test negatives and five had clinical follow-up for all and IFL for test negatives. Numbers with no SLN found were difficult to distinguish from those with negative SLN biopsies. The largest group of 11 studies using (99m)Tc/blue dye, ultrastaging and immunohistochemistry had a pooled sensitivity of 95.6% [95% confidence interval (CI) 91.5% to 98.1%] and a specificity of 100% (95% CI 99.0% to 100%). Mean SLN detection rates were 94.6% for (99m)Tc, 68.7% for blue dye and 97.7% for both. One study measured global health status quality of life (QoL) and found no difference between SLN biopsy and IFL. One patient preference evaluation showed that 66% preferred IFL rather than a 5% false-negative rate from SLN biopsy. For effectiveness, of 14,038 references, one randomised controlled trial, three case-control studies and 13 case series were found. Approximately 50% died from vulval cancer and 50% from other causes during follow-ups. Recurrences were in the ratio of approximately 4 : 2 : 1 vulval, groin and distant, with more recurrences in node-positive patients. No studies reported QoL. For cost per death averted, IFL was less costly and more effective than strategies using SLN biopsy. For morbidity-free survival and long-term morbidity-free survival, (99m)Tc with ultrastaging was most cost-effective. Strategies with blue dye only and H&E only were never cost-effective. The incremental cost-effectiveness ratio for (99m)Tc with ultrastaging compared with IFL was £4300 per case of morbidity-free survival and £7100 per long-term morbidity-free survival., Limitations: The main limitations of this study include the lack of good-quality evidence on accuracy, effectiveness and QoL. A large project such as this takes time to publish, so the most recent studies are not included., Conclusions: A sensitive and specific combined metastatic SLN detection test and information on generic QoL in vulval cancer is urgently required., Funding: The National Institute for Health Research Health Technology Assessment programme.

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.

Background: Cancer of the uterine cervix is a common cause of mortality in women. After initial treatment women may be symptom free, but the cancer may recur within a few years. It is uncertain whether it is more clinically effective to survey asymptomatic women for signs of recurrence or to await symptoms or signs before using imaging., Objectives: This project compared the diagnostic accuracy of imaging using positron emission tomography/computerised tomography (PET-CT) with that of imaging using CT or magnetic resonance imaging (MRI) alone and evaluated the cost-effectiveness of adding PET-CT as an adjunct to standard practice., Data Sources: Standard systematic review methods were used to obtain and evaluate relevant test accuracy and effectiveness studies. Databases searched included MEDLINE, EMBASE, Science Citation Index and The Cochrane Library. All databases were searched from inception to May 2010., Review Methods: Study quality was assessed using appropriately modified Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria. Included were any studies of PET-CT, MRI or CT compared with the reference standard of histopathological findings or clinical follow-up in symptomatic women suspected of having recurrent or persistent cervical cancer and in asymptomatic women a minimum of 3 months after completion of primary treatment. Subjective elicitation of expert opinion was used to supplement diagnostic information needed for the economic evaluation. The effectiveness of treatment with chemotherapy, radiotherapy, chemoradiotherapy, radical hysterectomy and pelvic exenteration was systematically reviewed. Meta-analysis was carried out in RevMan 5.1 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) and Stata version 11 (StataCorp LP, College Station, Texas, USA). A Markov model was developed to compare the relative cost-effectiveness using TreeAge Pro software version 2011 (TreeAge Software Inc., Evanston, IL, USA)., Results: For the diagnostic review, a total of 7524 citations were identified, of which 12 test accuracy studies were included in the review: six studies evaluated PET-CT, two evaluated MRI, three evaluated CT and one evaluated both MRI and CT. All studies were small and the majority evaluated imaging in women in whom recurrence was suspected on the basis of symptoms. The PET-CT studies evaluated local and distant recurrence and most used methods similar to current practice, whereas five of the six CT and MRI studies evaluated local recurrence only and not all employed currently used methods. Meta-analysis of PET-CT studies gave a sensitivity of 92.2% [95% confidence interval (CI) 85.1% to 96.0%] and a specificity of 88.1% (95% CI 77.9% to 93.9%). MRI sensitivities and specificities varied between 82% and 100% and between 78% and 100%, respectively, and CT sensitivities and specificities varied between 78% and 93% and between 0% and 95%, respectively. One small study directly compared PET-CT with older imaging methods and showed more true-positives and fewer false-negatives with PET-CT. The subjective elicitation from 21 clinical experts gave test accuracy results for asymptomatic and symptomatic women and the results for symptomatic women were similar to those from the published literature. Their combined opinions also suggested that the mean elicited increase in accuracy from the addition of PET-CT to MRI and/or CT was less than the elicited minimum important difference in accuracy required to justify the routine addition of PET-CT for the investigation of women after completion of primary treatment. For the effectiveness review, a total of 24,943 citations were identified, of which 62 studies were included (chemotherapy, 19 randomised controlled trials; radiotherapy or chemoradiotherapy, 16 case series; radical hysterectomy and pelvic exenteration, 27 case series). None provided the effectiveness of cisplatin monotherapy, the most commonly used chemotherapeutic agent in the NHS, compared with supportive care in a background of other treatment such as radiotherapy in recurrent and persistent cervical cancer. The model results showed that adding PET-CT to the current treatment strategy of clinical examination, MRI and/or CT scan was significantly more costly with only a minimal increase in effectiveness, with incremental cost-effectiveness ratios for all models being > £1M per quality-adjusted life-year (QALY) and the additional cost per additional case of recurrence being in the region of £600,000., Limitations: There was considerable uncertainty in many of the parameters used because of a lack of good-quality evidence in recurrent or persistent cervical cancer. The evidence on diagnostic and therapeutic impact incorporated in the economic model was poor and there was little information on surveillance of asymptomatic women., Conclusions: Given the current evidence available, the addition of PET-CT to standard practice was not found to be cost-effective in the diagnosis of recurrent or persistent cervical cancer. However, although probabilistic sensitivity analysis showed that the main conclusion about cost-ineffectiveness of PET-CT was firm given the range of assumptions made, should more reliable information become available on accuracy, therapeutic impact and effectiveness, and the cost of PET-CT reduce, this conclusion may need revision. Current guidelines recommending imaging for diagnosis using expensive methods such as PET-CT need to be reconsidered in the light of the above., Funding: The National Institute for Health Research Health Technology Assessment programme.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of prucalopride for the treatment of women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief. The ERG report is based on the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence as part of the single technology appraisal process. In the submission, quality-of-life data [Patient Assessment of Constipation Quality of Life (PAC-QOL) and Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaires] from trials of prucalopride were extrapolated to EQ-5D (European Quality of Life-5 Dimensions) data and used to inform effectiveness in an economic model. Response rates to prucalopride were derived from observed response rates in trials, defined as the proportion of patients achieving an average of three or more spontaneous complete bowel movements over the 4- or 12-week trial periods. Adult (18-64 years) and elderly (≥ 65 years) patients were considered separately in the model. Cost-effectiveness was determined from estimated improvements in EQ-5D and anticipated response rates, adjusted for baseline severity of chronic constipation. The ERG considered that the patients participating in these trials were not representative of those in the licensed indication. They were not all refractory to laxatives, and baseline EQ-5D scores showed a large spread in quality of life, with many patients experiencing little baseline dissatisfaction. The mapping of quality-of-life data from trials (PAC-QOL and PAC-SYM data) to EQ-5D was unclear and invalidated. The assumption of the long-term effectiveness and safety of prucalopride to 1 year was considered unjustified. There was no justification or sources given for coefficients used to predict effectiveness in the economic model, and no costs other than the cost of prucalopride were incorporated into the model. Owing to the many areas of uncertainty, particularly the effectiveness of prucalopride in the licensed patient group and its long-term effectiveness and safety, it was considered that the MS provided no evidence for whether prucalopride is effective or not in women with laxative-refractory chronic constipation. Further subgroup analysis of the actual patient group of interest may have better guided decision-making. However, long-term efficacy data, with validated estimates of quality of life incorporated in a well-founded model, would be important for an evidence-based judgement to be made.

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.

Background: Respiratory syncytial virus (RSV) is a seasonal infectious disease, with epidemics occurring annually from October to March in the UK. It is a very common infection in infants and young children and can lead to hospitalisation, particularly in those who are premature or who have chronic lung disease (CLD) or congenital heart disease (CHD). Palivizumab (Synagis®, MedImmune) is a monoclonal antibody designed to provide passive immunity against RSV and thereby prevent or reduce the severity of RSV infection. It is licensed for the prevention of serious lower respiratory tract infection caused by RSV in children at high risk. While it is recognised that a policy of using palivizumab for all children who meet the licensed indication does not meet conventional UK standards of cost-effectiveness, most clinicians feel that its use is justified in some children., Objectives: To use systematic review evidence to estimate the cost-effectiveness of immunoprophylaxis of RSV using palivizumab in different subgroups of children with or without CLD or CHD who are at high risk of serious morbidity from RSV infection., Data Sources: A systematic review of the literature and an economic evaluation was carried out. The bibliographic databases included the Cochrane Library [Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA)] and five other databases, from inception to 2009. Research registries of ongoing trials including Current Controlled Trials metaRegister, Clinical Trials.gov and the National Institute for Health Research Clinical Research Network Portfolio were also searched., Review Methods: Searches were conducted for prognostic and hospitalisation studies covering 1950-2009 (the original report searches conducted in 2007 covering the period 1950-2007 were rerun in August 2009 to cover the period 2007-9) and the database of all references from the original report was sifted to find any relevant studies that may have been missed. The risk factors identified from the systematic review of included studies were analysed and synthesised using stata. The base-case decision tree model developed in the original HTA journal publication [Health Technol Assess 2008;12(36)] was used to derive the cost-effectiveness of immunoprophylaxis of RSV using palivizumab in different subgroups of pre-term infants and young children who are at high risk of serious morbidity from RSV infection. Cost-effective spectra of prophylaxis with palivizumab compared with no prophylaxis for children without CLD/CHD, children with CLD, children with acyanotic CHD and children with cyanotic CHD were derived., Results: Thirteen studies were included in this analysis. Analysis of 16,128 subgroups showed that prophylaxis with palivizumab may be cost-effective [at a willingness-to-pay threshold of £30,000/quality-adjusted life-year (QALY)] for some subgroups. For example, for children without CLD or CHD, the cost-effective subgroups included children under 6 weeks old at the start of the RSV season who had at least two other risk factors that were considered in this report and were born at 24 weeks gestational age (GA) or less, but did not include children who were > 9 months old at the start of the RSV season or had a GA of > 32 weeks. For children with CLD, the cost-effective subgroups included children < 6 months old at the start of the RSV season who were born at 28 weeks GA or less, but did not include children who were > 21 months old at the start of the RSV season. For children with acyanotic CHD, the cost-effective subgroups included children < 6 months old at the start of the RSV season who were born at 24 weeks GA or less, but did not include children who were > 21 months old at the start of the RSV season. For children with cyanotic CHD, the cost-effective subgroups included children < 6 weeks old at the start of the RSV season who were born at 24 weeks GA or less, but did not include children who were > 12 months old at the start of the RSV season., Limitations: The poor quality of the studies feeding numerical results into this analysis means that the true cost-effectiveness may vary considerably from that estimated here. There is a risk that the relatively high mathematical precision of the point estimates of cost-effectiveness may be quite inaccurate because of poor-quality inputs., Conclusions: Prophylaxis with palivizumab does not represent good value for money based on the current UK incremental cost-effectiveness ratio threshold of £30,000/QALY when used unselectively in children without CLD/CHD or children with CLD or CHD. This subgroup analysis showed that prophylaxis with palivizumab may be cost-effective (at a willingness-to-pay threshold of £30,000/QALY) for some subgroups. In summary, the cost-effective subgroups for children who had no CLD or CHD must contain at least two other risk factors apart from GA and birth age. The cost-effective subgroups for children who had CLD or CHD do not necessarily need to have any other risk factors. Future research should be directed towards conducting much larger, better powered and better reported studies to derive better estimates of the risk factor effect sizes., Funding: This report was funded by the HTA programme of the National Institute for Health Research.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of certolizumab pegol (CZP) for adults with active rheumatoid arthritis (RA) that have not responded adequately to treatment with conventional disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX), in accordance with the licensed indication, based upon the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcome measures included American College of Rheumatology (ACR) 20, 50 and 70 response rates and quality of life measures after 3 months and 6 months of treatment. The ERG examined the submission's search strategies and considered they appeared comprehensive and that it was unlikely that relevant studies would have been missed. Only English language studies were considered in the submission and non-English language studies relevant to the decision problem may possibly have been ignored. The ERG analysed the first submitted economic model so as to itemise in detail clarification points that were brought to the attention of the manufacturer. In response the manufacturer submitted a modified cost-effectiveness analysis. The ERG undertook further analysis of this second model and other additional submitted evidence. The clinical evidence was derived from two multicentre blinded randomised controlled trials (RCTs) comparing CZP + MTX to placebo + MTX (the RAPID 1 and RAPID 2 trials). RAPID 1 lasted 52 weeks with 982 patients and RAPID 2 24 weeks with 619 patients. Evidence for clinical effectiveness of CZP in mono-therapy came from the 24-week FAST4WARD trial with 220 patients that compared CZP (400 mg every 4 weeks) versus placebo. The three key RCTs demonstrated statistically significant superiority of CZP + MTX versus placebo + MTX and of CZP versus placebo with respect to a variety of outcomes including ACR 20, ACR 50 and ACR 70 measures and quality of life measures at 3 and 6 months. On the basis of results from the indirect comparison meta-analyses, the manufacturer suggested that CZP may be at least as effective as other 'biological' DMARD (bDMARD) comparators and, in a few ACR measures at 3 and 6 months, more effective. CZP is an effective therapy for adult RA patients whose disease has failed to respond adequately to cDMARDs including MTX or who are intolerant of MTX. The cost-effectiveness of CZP relative to other bDMARDs is unclear because the economic modelling undertaken may have ignored relevant effectiveness data and potential differences between trial populations, and so may have included effectiveness results that were biased in favour of CZP; underestimated uncertainty in the relative effectiveness of compared DMARDs; and ignored the potential influence of differences between bDMARDs with regard to adverse events and their related costs and health impacts. The NICE guidance issued in October 2009 states that: the Committee is minded not to recommend certolizumab pegol as a treatment option for people with RA; and the Committee recommends that NICE asks the manufacturer of CZP for more information on the clinical effectiveness and cost-effectiveness of CZP for the treatment of people with RA. On receipt of this information and details of a patient access scheme NICE issued final guidance recommending CZP, under certain criteria, as a treatment option for people with RA.

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.

This paper presents a summary of the evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of rituximab with chemotherapy compared to chemotherapy only for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) 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. Evidence was available in the form of one open-label, ongoing, unpublished randomised controlled trial (RCT), REACH (Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia), conducted by the manufacturer, which compared rituximab with a fludarabine and cyclophosphamide combination (R-FC) to fludarabine and cyclophosphamide (FC) only. REACH was scheduled to run for 8 years; however, the data provided were immature, with a median observation time at the time of data analysis of 2.1 years. REACH provided evidence of prolonged progression free survival with R-FC compared to FC (10 months, investigators' data), but no evidence of an overall survival benefit with R-FC. Patients refractory to fludarabine and with prior rituximab exposure were excluded from REACH and no controlled studies were identified by the ERG for these patient groups. The ERG had concerns about the structure of the economic model submitted by the manufacturer, which did not allow improvement in quality of life from treatment while in a progressed state. The manufacturer's model further assumed a divergence in cumulative deaths between the R-FC and FC treatment arms from the outset, which did not accord with observed data from REACH. When the survival advantage was removed, the manufacturer's base-case incremental cost-effectiveness ratio (ICER) changed from 15,593 pounds to between 40,000 pounds and 42,000 pounds per quality-adjusted life-year (QALY). With no survival advantage, the ICER became sensitive to changes in utility. There was no good empirical evidence on the utility of CLL patients in different states. Allowing for the possibility of a survival advantage with rituximab (although not supported by current evidence), the ERG performed further modelling, which found that rituximab would be cost-effective at 20,000 pounds/QALY (30,000 pounds/QALY) if a reduction in survival advantage relative to the manufacturer's base case of 40% (80%) was assumed. The guidance issued by NICE in July 2010 as a result of the STA recommends rituximab with FC for people with relapsed or refractory chronic lymphocytic leukaemia, except when the condition is refractory to fludarabine or where there has been previous treatment with rituximab.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of cetuximab for the first-line treatment of metastatic colorectal cancer (mCRC), 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 ERG project ran between 22 January 2008 and 4 November 2008. The clinical evidence came from two unpublished randomised controlled trials (RCTs) of cetuximab plus chemotherapy versus chemotherapy alone in the first-line treatment of mCRC. A third RCT submitted later compared cetuximab with irinotecan in combination with 5-fluorouracil (5-FU) and folinic acid (FA) and cetuximab with oxaliplatin in combination with 5-FU and FA in patients with mCRC with liver metastases only. No published economic evaluations of cetuximab for first-line chemotherapy in mCRC were identified in the submission. A de novo model examined the cost-effectiveness of cetuximab in patients with mCRC that was epidermal growth factor receptor positive, k-ras wild type and with liver metastases. The main source of clinical effectiveness evidence came from the first two RCTs which provided follow up information for 1-2 years. Secondary information was used to estimate survival for a further 22 years. The model focused on the patients for whom the treatment had been licensed. This limited the applicability of the model to the NHS setting in which patients would be a mixture of k-ras wild type and mutations and also a mixture of patients with liver metastases and other metastases. The difference in progression-free survival for the two trials was between 0.5 to 1.2 months over a 7-10 month period. Eight months' treatment with cetuximab, given as an initial loading dose and then weekly until progression, would cost around 22,932 pounds for an average man and 18,427 pounds for an average woman. It is uncertain whether this constitutes good value for money. The guidance issued by NICE on 25 September 2008 stated that cetuximab was not recommended for the first-line treatment of mCRC and people currently receiving cetuximab for the first-line treatment of mCRC should have the option to continue treatment until they and their clinicians consider it appropriate to stop.

Objectives: To establish the clinical effectiveness and cost-effectiveness of structural neuroimaging [structural magnetic resonance imaging (MRI) or computed tomography (CT) scanning] for all patients with psychosis, particularly a first episode of psychosis, relative to the current UK practice of selective screening only where it is clinically indicated., Data Sources: Major electronic databases were searched from inception to November 2006., Review Methods: A systematic review of studies reporting the additional diagnostic benefit of structural MRI, CT or combinations of these in patients with psychosis was conducted. The economic assessment consisted of a systematic review of economic evaluations and the development of a threshold analysis to predict the gain in quality-adjusted life-years (QALYs) required to make neuroimaging cost-effective at commonly accepted threshold levels (20,000 pounds and 30,000 pounds per QALY). Sensitivity analyses of several parameters including prevalence of psychosis were performed., Results: The systematic review included 24 studies of a diagnostic before-after type of design evaluating the clinical benefit of CT, structural MRI or combinations in treatment-naive, first-episode or unspecified psychotic patients, including one in schizophrenia patients resistant to treatment. Also included was a review of published case reports of misidentification syndromes. Almost all evidence was in patients aged less than 65 years. In most studies, structural neuroimaging identified very little that would influence patient management that was not suspected based on a medical history and/or physical examination and there were more incidental findings. In the four MRI studies, approximately 5% of patients had findings that would influence clinical management, whereas in the CT studies, approximately 0.5% of patients had these findings. The review of misidentification syndromes found that 25% of CT scans affected clinical management, but this may have been a selected and therefore unrepresentative sample. A threshold analysis with a 1-year time horizon was undertaken. This combined the incremental cost of routine scanning with a threshold cost per QALY value of 20,000 pounds and 30,000 pounds to predict the QoL gain required to meet these threshold values. Routine scanning versus selective scanning appears to produce different results for MRI and CT. With MRI scanning the incremental cost is positive, ranging from 37 pounds to 150 pounds; however, when scanning routinely using CT, the result is cost saving, ranging from 7 pounds to 108 pounds with the assumption of a 1% prevalence rate of tumours/cysts or other organic causes amenable to treatment. This means that for the intervention to be viewed as cost-effective, the QALY gain necessary for MRI scanning is 0.002-0.007 and with CT scanning the QALY loss that can be tolerated is between 0.0003 and 0.0054 using a 20,000 pounds threshold value. These estimates were subjected to sensitivity analysis. With a 3-month time delay, MRI remains cost-incurring with a small gain in QoL required for the intervention to be cost-effective; routine scanning with CT remains cost-saving. When the sensitivity of CT is varied to 50%, routine scanning is both cost-incurring or cost-saving depending on the scenario. Finally, the results have been shown to be sensitive to the assumed prevalence rate of brain tumours in a psychotic population., Conclusions: The evidence to date suggests that if screening with structural neuroimaging was implemented in all patients presenting with psychotic symptoms, little would be found to affect clinical management in addition to that suspected by a full clinical history and neurological examination. From an economic perspective, the outcome is not clear. The strategy of neuroimaging for all is either cost-incurring or cost-saving (dependent upon whether MRI or CT is used) if the prevalence of organic causes is around 1%. However, these values are nested within a number of assumptions, and so have to be interpreted with caution. The main research priorities are to monitor the current use of structural neuroimaging in psychosis in the NHS to identify clinical triggers to its current use and subsequent outcomes; to undertake well-conducted diagnostic before-and-after studies on representative populations to determine the clinical utility of structural neuroimaging in this patient group, and to determine whether the most appropriate structural imaging modality in psychosis should be CT or MRI.

Objectives: To investigate the accuracy of predictive tests for pre-eclampsia and the effectiveness of preventative interventions for pre-eclampsia. Also to assess the cost-effectiveness of strategies (test-intervention combinations) to predict and prevent pre-eclampsia., Data Sources: Major electronic databases were searched to January 2005 at least., Review Methods: Systematic reviews were carried out for test accuracy and effectiveness. Quality assessment was carried out using standard tools. For test accuracy, meta-analyses used a bivariate approach. Effectiveness reviews were conducted under the auspices of the Cochrane Pregnancy and Childbirth Group and used standard Cochrane review methods. The economic evaluation was from an NHS perspective and used a decision tree model., Results: For the 27 tests reviewed, the quality of included studies was generally poor. Some tests appeared to have high specificity, but at the expense of compromised sensitivity. Tests that reached specificities above 90% were body mass index greater than 34, alpha-foetoprotein and uterine artery Doppler (bilateral notching). The only Doppler test with a sensitivity of over 60% was resistance index and combinations of indices. A few tests not commonly found in routine practice, such as kallikreinuria and SDS-PAGE proteinuria, seemed to offer the promise of high sensitivity, without compromising specificity, but these would require further investigation. For the 16 effectiveness reviews, the quality of included studies was variable. The largest review was of antiplatelet agents, primarily low-dose aspirin, and included 51 trials (36,500 women). This was the only review where the intervention was shown to prevent both pre-eclampsia and its consequences for the baby. Calcium supplementation also reduced the risk of pre-eclampsia, but with some uncertainty about the impact on outcomes for the baby. The only other intervention associated with a reduction in RR of pre-eclampsia was rest at home, with or without a nutritional supplement, for women with normal blood pressure. However, this review included just two small trials and its results should be interpreted with caution. The cost of most of the tests was modest, ranging from 5 pounds for blood tests such as serum uric acid to approximately 20 pounds for Doppler tests. Similarly, the cost of most interventions was also modest. In contrast, the best estimate of additional average cost associated with an average case of pre-eclampsia was high at approximately 9000 pounds. The results of the modelling revealed that prior testing with the test accuracy sensitivities and specificities identified appeared to offer little as a way of improving cost-effectiveness. Based on the evidence reviewed, none of the tests appeared sufficiently accurate to be clinically useful and the results of the model favoured no-test/treat-all strategies. Rest at home without any initial testing appeared to be the most cost-effective 'test-treatment' combination. Calcium supplementation to all women, without any initial testing, appeared to be the second most cost-effective. The economic model provided little support that any form of Doppler test has sufficiently high sensitivity and specificity to be cost-effective for the early identification of pre-eclampsia. It also suggested that the pattern of cost-effectiveness was no different in high-risk mothers than the low-risk mothers considered in the base case., Conclusions: The tests evaluated are not sufficiently accurate, in our opinion, to suggest their routine use in clinical practice. Calcium and antiplatelet agents, primarily low-dose aspirin, were the interventions shown to prevent pre-eclampsia. The most cost-effective approach to reducing pre-eclampsia is likely to be the provision of an effective, affordable and safe intervention applied to all mothers without prior testing to assess levels of risk. It is probably premature to suggest the implementation of a treat-all intervention strategy at present, however the feasibility and acceptability of this to women could be explored. Rigorous evaluation is needed of tests with modest cost whose initial assessments suggest that they may have high levels of both sensitivity and specificity. Similarly, there is a need for high-quality, adequately powered randomised controlled trials to investigate whether interventions such as advice to rest are indeed effective in reducing pre-eclampsia. In future, an economic model should be developed that considers not just pre-eclampsia, but other related outcomes, particularly those relevant to the infant such as perinatal death, preterm birth and small for gestational age. Such a modelling project should make provision for primary data collection on the safety of interventions and their associated costs.

Objectives: To examine the clinical effectiveness and cost-effectiveness of the newer immunosuppressive drugs for renal transplantation: basiliximab, daclizumab, tacrolimus, mycophenolate (mofetil and sodium) and sirolimus., Data Sources: Electronic databases. Industry submissions. Current Clinical Trials register. Cochrane Collaboration Renal Disease Group., Review Methods: The review followed the InterTASC standards. Each of the five company submissions to the National Institute for Clinical Excellence (NICE) contained cost-effectiveness models, which were evaluated by using a critique covering (1) model checking, (2) a detailed model description and (3) model rerunning., Results: For induction therapy, three randomised controlled trials (RCTs) found that daclizumab significantly reduced the incidence of biopsy-confirmed acute rejection and patient survival at 6 months/1 year compared with placebo, but not compared with the monoclonal antibody OKT3. There was no significant gain in patient survival or graft loss at 3 years. The incidence of side-effects with daclizumab reduced compared to OKT3. Eight RCTs found that basiliximab significantly improved 6-month/1-year biopsy-confirmed acute rejection compared to placebo, but not compared to either ATG or OKT3. There was no significant gain in either 1-year patient survival or graft loss. The incidence of side-effects with basiliximab was not significantly different compared to OKT3/ATG. For initial/maintenance therapy, 13 RCTs found that tacrolimus reduced the 6-month/1-year incidence of biopsy-proven acute rejection compared to ciclosporin. There was no significant improvement in either 1-year or long-term (up to 5 years) graft loss or patient survival. The acute rejection benefit of tacrolimus over ciclosporin appeared to be equivalent for Sandimmun and Neoral. There were important differences in the side-effect profile of tacrolimus and ciclosporin. Seven RCTs found that mycophenolate mofetil (MMF) reduced the incidence of acute rejection. There was no significant difference in patient survival or graft loss at 1-year or 3-year follow-up. There appeared to be differences in the side-effect profiles of MMF and azathioprine (AZA). No RCTs comparing MMF with AZA were identified. One RCT compared mycophenolate sodium (MPS) to MMF and reported no difference between the two drugs in 1-year acute rejection rate, graft survival, patient survival or side-effect profile. Two RCTs suggest that addition of sirolimus to a ciclosporin-based initial/maintenance therapy reduces 1-year acute rejections in comparison to a ciclosporin (Neoral) dual therapy alone and substituting azathioprine with sirolimus in initial/maintenance therapy reduces the incidence of acute rejection. Graft and patient survival were not significantly different with either sirolimus regimen. Adding sirolimus increases the incidence of side-effects. The side-effect profiles of azathioprine and sirolimus appear to be different. For the treatment of acute rejection, three RCTs suggested that both tacrolimus and MMF reduce the incidence of subsequent acute rejection and the need for additional drug therapy. Only one RCT and one subgroup analysis in children (<18 years) were identified comparing ciclosporin to tacrolimus and sirolimus, respectively., Conclusions: The newer immunosuppressant drugs (basiliximab, daclizumab, tacrolimus and MMF) consistently reduced the incidence of short-term (1-year) acute rejection compared with conventional immunosuppressive therapy. The independent use of basiliximab, daclizumab, tacrolimus and MMF was associated with a similar absolute reduction in 1-year acute rejection rate (approximately 15%). However, the effects of these drugs did not appear to be additive (e.g. benefit of tacrolimus with adjuvant MMF was 5% reduction in acute rejection rate compared with 15% reduction with adjuvant AZA). Thus, the addition of one of these drugs to a baseline immunosuppressant regimen was likely to affect adversely the incremental cost-effectiveness of the addition of another. The trials did not assess how the improvement in short-term outcomes (e.g. acute rejection rate or measures of graft function), together with the side-effect profile associated with each drug, translated into changes in patient-related quality of life. Moreover, given the relatively short duration of trials, the impact of the newer immunosuppressants on long-term graft loss and patient survival remains uncertain. The absence of both long-term outcome and quality of life from trial data makes assessment of the clinical and cost-effectiveness on the newer immunosuppressants contingent on modelling based on extrapolations from short-term trial outcomes. The choice of the most appropriate short-term outcome (e.g. acute rejection rate or measures of graft function) for such modelling remains a matter of clinical and scientific debate. The decision to use acute rejection in the meta-model in this report was based on the findings of a systematic review of the literature of predictors of long-term graft outcome. Only a very small proportion of the RCTs identified in this review assessed patient-focused outcomes such as quality of life. Since immunosuppressive drugs have both clinical benefits and specific side-effects, the balance of these harms and benefits could best be quantified through future trials using quality of life measures. The design of future trials should be considered with a view to the impact of drugs on particular renal transplant groups, particularly higher risk individuals and children. Finally, there is a need for improved reporting of methodological details of future trials, such as the method of randomisation and allocation concealment. A number of issues exist around registry data, for example the use of multiple drug regimens and the need to assess the long-term outcomes. An option is the use of observational registry data including, if possible, prospective data on all consecutive UK renal transplant patients. Data capture for each patient should include immunosuppressant regimens, clinical and patient-related outcomes and patient demographics.

Background: Coronary artery stents are prosthetic linings inserted into coronary arteries via a catheter to widen the artery and increase blood flow to ischaemic heart muscle. They are used in the treatment of ischaemic heart disease (IHD). IHD is a major cause of morbidity and mortality (123,000 deaths per annum) in the UK and a major cost to the NHS. Clinical effects of IHD include subacute manifestations (stable and unstable angina) and acute manifestations (particularly myocardial infarction [MI]). Treatment includes attention to risk factors, drug therapy, percutaneous invasive interventions (PCIs) (including percutaneous transluminal coronary angioplasty [PTCA] and stents) and coronary artery bypass graft surgery (CABG). In the last decade there has been a steady and significant increase in the rate of PCIs for IHD. In the UK, rates per million population increased from 174 in 1991 to 437 in 1998. Stents are now used in about 70% of PCIs. Data from the rest of Europe suggest there is potential for PCI and stent rates to increase considerably. In the UK there is evidence of under-provision and inequity of access to revascularisation procedures., Objectives: The following questions were addressed. 1. What are the effects and effectiveness of elective stent insertion versus PTCA in subacute IHD, particularly stable angina and unstable angina? 2. What are the effects and effectiveness of elective stent insertion versus CABG in subacute IHD, particularly stable angina and unstable angina? 3. What are the effects and effectiveness of elective stent insertion versus PTCA in acute MI (AMI)? 4. What are best estimates of UK cost for elective stent insertion, PTCA and CABG in the circumstances of review questions 1 to 3? 5. What are best estimates of cost-effectiveness and cost-utility for elective stent insertion relative to PTCA or CABG in the circumstances of review questions 1 to 3?, Methods: A systematic review addressing the objectives was undertaken., Data Sources: A search was made for RCTs comparing stents (inserted during a PTCA procedure) with PTCA alone or with CABG in any manifestation of IHD. The search strategy covered the period from 1990 to November 1999 and included searches of electronic databases (MEDLINE, EMBASE, BIDS ISI, The Cochrane Library), Internet sites, and hand-searches of cardiology conference abstracts and 1999 issues of cardiology journals. Lead researchers and local clinical experts were contacted. Manufacturers' submissions to the National Institute for Clinical Excellence were searched. The search strategy was expanded to look for relevant economic analyses and information to inform the economic model (including searching MEDLINE, the NHS Economic Evaluation Database and the Database of Abstracts of Reviews of Effectiveness). Searches focused on research that reported costs and quality of life data associated with IHD and interventional cardiology., Study Selection: For the review of clinical effectiveness, inclusion criteria were: (i) RCT design; (ii) study population comprising adults with IHD in native or graft vessels (including patients with subacute IHD or AMI); (iii) procedure involving elective insertion of coronary artery stents; (iv) elective PTCA (including PTCA with provisional stenting) or CABG as comparator; (v) outcomes defined as one or more of: combined event rate (or event-free survival), death, MI, angina, target vessel revascularisation, CABG, repeat PTCA, angiographic outcomes; (vi) trials that had closed and reported results for all or almost all recruited patients. For the economic evaluation, studies of adults with IHD were included if they were of the following types: studies reporting UK costs; comparative economic evaluation combining both costs and outcomes; economic evaluations reporting costs and outcomes separately for the years 1998 and 1999 (to ensure current practice was included).(ABSTRACT TRUNCATED)