Optical coherence tomography for the diagnosis of neovascular age-related macular degeneration: a systematic review.

UNLABELLED: The purpose is to study the diagnostic performance of optical coherence tomography (OCT) and alternative diagnostic tests for neovascular age-related macular degeneration (nAMD). Methods employed are as follows:systematic review and meta-analysis; INDEX TEST: OCT including time-domain (TD-OCT) and the most recently developed spectral domain (SD-OCT); comparator tests: visual acuity, clinical evaluation (slit lamp), Amsler chart, colour fundus photographs, infra-red reflectance, red-free images/blue reflectance, fundus autofluorescence imaging (FAF), indocyanine green angiography (ICGA), preferential hyperacuity perimetry (PHP), and microperimetry; reference standard: fundus fluorescein angiography. Databases searched included MEDLINE, MEDLINE In Process, EMBASE, Biosis, SCI, the Cochrane Library, DARE, MEDION, and HTA database. Last literature searches: March 2013. Risk of bias assessed using QUADAS-2. Meta-analysis models were fitted using hierarchical summary receiver operating characteristic (HSROC) curves. Twenty-two studies (2 abstracts and 20 articles) enrolling 2124 participants were identified, reporting TD-OCT (12 studies), SD-OCT (1 study), ICGA (8 studies), PHP (3 studies), Amsler grid, colour fundus photography and FAF (1 study each). Most studies were considered to have a high risk of bias in the patient selection (55%, 11/20), and flow and timing (40%, 8/20) domains. In a meta-analysis of TD-OCT studies, sensitivity and specificity (95% CI) were 88% (46-98%) and 78% (64-88%), respectively. There was insufficient information to undertake meta-analysis for other tests. TD-OCT is a sensitive test for detecting nAMD, although specificity was only moderate. Data on SD-OCT are sparse. Diagnosis of nAMD should not rely solely on OCT.

Systematic review of the clinical effectiveness and cost-effectiveness, and economic evaluation, of denosumab for the treatment of bone metastases from solid tumours.

BACKGROUND: Denosumab offers an alternative, or additional, treatment for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumours. OBJECTIVES: The aim of this review was to assess the clinical effectiveness and cost-effectiveness of denosumab, within its licensed indication, for the prevention of SREs in patients with bone metastases from solid tumours. DATA SOURCES: Databases searched were MEDLINE (1948 to April 2011), EMBASE (1980 to March 2011), The Cochrane Library (all sections; Issue 1, 2011) and Web of Science with Conference Proceedings (1970 to May 2011). REVIEW METHODS: Only randomised controlled trials (RCTs) assessing denosumab, bisphosphonates (BPs) or best supportive care (BSC) in patients with bone metastases were included. Systematic reviews and observational studies were used for safety and quality-of-life assessments. Study quality was assessed using the Cochrane risk of bias tool. Studies suitable for meta-analysis were synthesised using network meta-analysis (NMA). A systematic review was conducted for cost, quality-of-life and cost-effectiveness studies. The results of this informed the cost-utility modelling. This principally estimated the cost-effectiveness of denosumab relative to zoledronic acid for when BPs are currently recommended and relative to BSC when BPs are not recommended or are contraindicated. RESULTS: A literature search identified 39 studies (eight suitable for NMA). Denosumab was effective in delaying time to first SRE and reducing the risk of multiple SREs compared with zoledronic acid. Generally speaking, denosumab was similar to zoledronic acid for quality of life, pain, overall survival and safety. The NMA demonstrated that denosumab was more effective in delaying SREs than placebo, but was limited by numerous uncertainties. Cost-utility modelling results for denosumab relative to zoledronic acid were driven by the availability of the patient access scheme (PAS) for denosumab. Without this, denosumab was not estimated to be cost-effective compared with zoledronic acid. With it, the cost-effectiveness ranged between dominance for breast and prostate cancer, to between £5400 and £15,300 per quality-adjusted life-year (QALY) for other solid tumours (OSTs) including non-small cell lung cancer (NSCLC) and £12,700 per QALY for NSCLC. Owing to small patient gains estimated, the cost-effectiveness of denosumab was very sensitive to the zoledronic acid price. Denosumab was not estimated to be cost-effective compared with BSC. LIMITATIONS: Only subgroup data were available for denosumab for NSCLC, and OSTs excluding NSCLC. The NMA was subject to numerous uncertainties. Owing to small patient gains estimated, the cost-effectiveness of denosumab was very sensitive to the zoledronic acid price. CONCLUSION: Denosumab, compared with zoledronic acid and placebo, is effective in delaying SREs, but is similar with regard to quality of life and pain. Cost-effectiveness showed that without the PAS denosumab was not estimated to be cost-effective relative to either zoledronic acid or BSC. With the PAS, denosumab was estimated to be cost-effective relative to zoledronic acid but not BSC. STUDY REGISTRATION: PROSPERO number CRD42011001418. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The diagnostic accuracy and cost-effectiveness of magnetic resonance spectroscopy and enhanced magnetic resonance imaging techniques in aiding the localisation of prostate abnormalities for biopsy: a systematic review and economic evaluation.

BACKGROUND: In the UK, prostate cancer (PC) is the most common cancer in men. A diagnosis can be confirmed only following a prostate biopsy. Many men find themselves with an elevated prostate-specific antigen (PSA) level and a negative biopsy. The best way to manage these men remains uncertain. OBJECTIVES: To assess the diagnostic accuracy of magnetic resonance spectroscopy (MRS) and enhanced magnetic resonance imaging (MRI) techniques [dynamic contrast-enhanced MRI (DCE-MRI), diffusion-weighted MRI (DW-MRI)] and the clinical effectiveness and cost-effectiveness of strategies involving their use in aiding the localisation of prostate abnormalities for biopsy in patients with prior negative biopsy who remain clinically suspicious for harbouring malignancy. DATA SOURCES: Databases searched--MEDLINE (1946 to March 2012), MEDLINE In-Process & Other Non-Indexed Citations (March 2012), EMBASE (1980 to March 2012), Bioscience Information Service (BIOSIS; 1995 to March 2012), Science Citation Index (SCI; 1995 to March 2012), The Cochrane Library (Issue 3 2012), Database of Abstracts of Reviews of Effects (DARE; March 2012), Medion (March 2012) and Health Technology Assessment database (March 2012). REVIEW METHODS: Types of studies: direct studies/randomised controlled trials reporting diagnostic outcomes. INDEX TESTS: MRS, DCE-MRI and DW-MRI. Comparators: T2-weighted magnetic resonance imaging (T2-MRI), transrectal ultrasound-guided biopsy (TRUS/Bx). Reference standard: histopathological assessment of biopsied tissue. A Markov model was developed to assess the cost-effectiveness of alternative MRS/MRI sequences to direct TRUS-guided biopsies compared with systematic extended-cores TRUS-guided biopsies. A health service provider perspective was adopted and the recommended 3.5% discount rate was applied to costs and outcomes. RESULTS: A total of 51 studies were included. In pooled estimates, sensitivity [95% confidence interval (CI)] was highest for MRS (92%; 95% CI 86% to 95%). Specificity was highest for TRUS (imaging test) (81%; 95% CI 77% to 85%). Lifetime costs ranged from £3895 using systematic TRUS-guided biopsies to £4056 using findings on T2-MRI or DCE-MRI to direct biopsies (60-year-old cohort, cancer prevalence 24%). The base-case incremental cost-effectiveness ratio for T2-MRI was <£30,000 per QALY (all cohorts). Probabilistic sensitivity analysis showed high uncertainty surrounding the incremental cost-effectiveness of T2-MRI in moderate prevalence cohorts. The cost-effectiveness of MRS compared with T2-MRI and TRUS was sensitive to several key parameters. LIMITATIONS: Non-English-language studies were excluded. Few studies reported DCE-MRI/DW-MRI. The modelling was hampered by limited data on the relative diagnostic accuracy of alternative strategies, the natural history of cancer detected at repeat biopsy, and the impact of diagnosis and treatment on disease progression and health-related quality of life. CONCLUSIONS: MRS had higher sensitivity and specificity than T2-MRI. Relative cost-effectiveness of alternative strategies was sensitive to key parameters/assumptions. Under certain circumstances T2-MRI may be cost-effective compared with systematic TRUS. If MRS and DW-MRI can be shown to have high sensitivity for detecting moderate/high-risk cancer, while negating patients with no cancer/low-risk disease to undergo biopsy, their use could represent a cost-effective approach to diagnosis. However, owing to the relative paucity of reliable data, further studies are required. In particular, prospective studies are required in men with suspected PC and elevated PSA levels but previously negative biopsy comparing the utility of the individual and combined components of a multiparametric magnetic resonance (MR) approach (MRS, DCE-MRI and DW-MRI) with both a MR-guided/-directed biopsy session and an extended 14-core TRUS-guided biopsy scheme against a reference standard of histopathological assessment of biopsied tissue obtained via saturation biopsy, template biopsy or prostatectomy specimens. STUDY REGISTRATION: PROSPERO number CRD42011001376. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Systematic review and economic modelling of the relative clinical benefit and cost-effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with localised prostate cancer.

BACKGROUND: Complete surgical removal of the prostate, radical prostatectomy, is the most frequently used treatment option for men with localised prostate cancer. The use of laparoscopic (keyhole) and robot-assisted surgery has improved operative safety but the comparative effectiveness and cost-effectiveness of these options remains uncertain. OBJECTIVE: This study aimed to determine the relative clinical effectiveness and cost-effectiveness of robotic radical prostatectomy compared with laparoscopic radical prostatectomy in the treatment of localised prostate cancer within the UK NHS. DATA SOURCES: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, BIOSIS, Science Citation Index and Cochrane Central Register of Controlled Trials were searched from January 1995 until October 2010 for primary studies. Conference abstracts from meetings of the European, American and British Urological Associations were also searched. Costs were obtained from NHS sources and the manufacturer of the robotic system. Economic model parameters and distributions not obtained in the systematic review were derived from other literature sources and an advisory expert panel. REVIEW METHODS: Evidence was considered from randomised controlled trials (RCTs) and non-randomised comparative studies of men with clinically localised prostate cancer (cT1 or cT2); outcome measures included adverse events, cancer related, functional, patient driven and descriptors of care. Two reviewers abstracted data and assessed the risk of bias of the included studies. For meta-analyses, a Bayesian indirect mixed-treatment comparison was used. Cost-effectiveness was assessed using a discrete-event simulation model. RESULTS: The searches identified 2722 potentially relevant titles and abstracts, from which 914 reports were selected for full-text eligibility screening. Of these, data were included from 19,064 patients across one RCT and 57 non-randomised comparative studies, with very few studies considered at low risk of bias. The results of this study, although associated with some uncertainty, demonstrated that the outcomes were generally better for robotic than for laparoscopic surgery for major adverse events such as blood transfusion and organ injury rates and for rate of failure to remove the cancer (positive margin) (odds ratio 0.69; 95% credible interval 0.51 to 0.96; probability outcome favours robotic prostatectomy = 0.987). The predicted probability of a positive margin was 17.6% following robotic prostatectomy compared with 23.6% for laparoscopic prostatectomy. Restriction of the meta-analysis to studies at low risk of bias did not change the direction of effect but did decrease the precision of the effect size. There was no evidence of differences in cancer-related, patient-driven or dysfunction outcomes. The results of the economic evaluation suggested that when the difference in positive margins is equivalent to the estimates in the meta-analysis of all included studies, robotic radical prostatectomy was on average associated with an incremental cost per quality-adjusted life-year that is less than threshold values typically adopted by the NHS (£30,000) and becomes further reduced when the surgical capacity is high. LIMITATIONS: The main limitations were the quantity and quality of the data available on cancer-related outcomes and dysfunction. CONCLUSIONS: This study demonstrated that robotic prostatectomy had lower perioperative morbidity and a reduced risk of a positive surgical margin compared with laparoscopic prostatectomy although there was considerable uncertainty. Robotic prostatectomy will always be more costly to the NHS because of the fixed capital and maintenance charges for the robotic system. Our modelling showed that this excess cost can be reduced if capital costs of equipment are minimised and by maintaining a high case volume for each robotic system of at least 100-150 procedures per year. This finding was primarily driven by a difference in positive margin rate. There is a need for further research to establish how positive margin rates impact on long-term outcomes. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Elucigene FH20 and LIPOchip for the diagnosis of familial hypercholesterolaemia: a systematic review and economic evaluation.

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic condition causing a high risk of coronary heart disease. The prevalence of this disease is about 1 in 500 in the UK, affecting about 120,000 people across the whole of the UK. Current guidelines recommend DNA testing, however, these guidelines are poorly implemented, therefore 102,000 or 85% of this group remain undiagnosed. OBJECTIVES: To assess the diagnostic accuracy, effect on patient outcomes and cost-effectiveness of Elucigene FH20 and LIPOchip for the diagnosis of FH. DATA SOURCES: Electronic databases including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, BIOSIS, Science Citation Index, Conference Proceedings Citation Index - Science and Cochrane Controlled Trials Register were searched until January 2011. REVIEW METHODS: A systematic review of the literature on diagnostic accuracy was carried out according to standard methods. An economic model was constructed to assess the cost-effectiveness of alternative diagnostic strategies for the confirmation of clinically diagnosed FH in index cases and for the identification and subsequent testing of first-, second- and possibly third-degree biological relatives of the index case. Twelve strategies were evaluated linking diagnostic accuracy to treatment outcomes and hence quality-adjusted life-years (QALYs). Deterministic and probabilistic sensitivity analyses were undertaken to investigate model and parameter uncertainty. RESULTS: Fifteen studies were included for diagnostic accuracy; three reported Elucigene FH20, five reported LIPOchip, four reported low-density lipoprotein cholesterol (LDL-C) tests and three reported an age- and gender-specific LDL-C test against a reference standard of comprehensive genetic analysis (CGA). Sensitivity ranged from 44% to 52% for Elucigene FH20 and from 33.3% to 94.5% for various versions of LIPOchip in detecting FH-causing mutations in patients with a clinical diagnosis of FH. For LIPOchip version 10 (designed to detect 189 UK specific mutations), sensitivity would be 78.5% (based on single-centre data - Progenika, personal communication). For all other Elucigene FH20 or LIPOchip studies (apart from one LIPOchip study), specificity could not be calculated as no false-positive results could be derived from the given data. The LDL-C test was generally reported to be highly sensitive but with low specificity. For age- and gender-specific LDL-C cut-offs for cascade testing, sensitivity ranged from 68% to 96%. One UK-based study reported sensitivity of 91% and specificity of 93%. For the cost-effectiveness review, only one study reporting cost-effectiveness of any one of the comparators for this assessment was identified. Pre-screen strategies such as Elucigene FH20 followed by CGA were not cost-effective and were dominated by the single more comprehensive tests (e.g. CGA). Of the non-dominated strategies, Elucigene FH20, LIPOchip platform (Spain) and CGA were all cost-effective with associated incremental cost-effectiveness ratios (ICERs) relative to LDL-C of dominance (test is less costly and more effective), £871 and £1030 per QALY gained respectively. CGA generates the greatest QALY gain and, although other tests have lower ICERs relative to LDL-C, this is at the expense of QALY loss compared with the CGA test. Probabilistic sensitivity analysis shows that CGA is associated with an almost 100% probability of cost-effectiveness at the conventional value of willingness to pay of £20,000 per QALY gain. LIMITATIONS: There was much uncertainty regarding the diagnostic accuracy of the included tests, with wide variation in sensitivity across reported studies. A lack of published information for the most recent version of LIPOchip created additional uncertainty, especially in relation to the chip's ability to detect copy number changes. For the economic modelling, we aimed to choose the best studies for the base-case sensitivity of the tests; however, a number of informed choices based on clinical expert opinion had to be made in the absence of published studies for a number of other parameters in the modelling. This adds some uncertainty to our results, although it is unlikely that these would be sufficient in magnitude to alter our main results and conclusions. CONCLUSIONS: As targeted tests designed to detect a limited number of genetic mutations, Elucigene FH20 and LIPOchip cannot detect all cases of FH, in contrast with CGA. CGA is therefore the most effective test in terms of sensitivity and QALY gain, and is also highly cost-effective with an associated ICER of £1030 per QALY gain relative to current practice (LDL-C). Other tests such as Elucigene FH20 and LIPOchip are also cost-effective; however, because of inferior sensitivity compared with CGA, these tests offer cost savings but at the expense of large QALY losses compared with CGA. Further prospective multicentred studies are required to evaluate the diagnostic accuracy of new and emerging tests for FH with the LDL-C test in patients with a clinical diagnosis based on the Simon Broome criteria. Such studies should verify both test-positive and -negative results against a reference standard of CGA and should include a full economic evaluation. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The clinical effectiveness and cost-effectiveness of different surveillance mammography regimens after the treatment for primary breast cancer: systematic reviews registry database analyses and economic evaluation.

BACKGROUND: Following primary breast cancer treatment, the early detection of ipsilateral breast tumour recurrence (IBTR) or ipsilateral secondary cancer in the treated breast and detection of new primary cancers in the contralateral breast is beneficial for survival. Surveillance mammography is used to detect these cancers, but the optimal frequency of surveillance and the length of follow-up are unclear. OBJECTIVES: To identify feasible management strategies for surveillance and follow-up of women after treatment for primary breast cancer in a UK setting, and to determine the effectiveness and cost-effectiveness of differing regimens. METHODS: A survey of UK breast surgeons and radiologists to identify current surveillance mammography regimens and inform feasible alternatives; two discrete systematic reviews of evidence published from 1990 to mid 2009 to determine (i) the clinical effectiveness and cost-effectiveness of differing surveillance mammography regimens for patient health outcomes and (ii) the test performance of surveillance mammography in the detection of IBTR and metachronous contralateral breast cancer (MCBC); statistical analysis of individual patient data (West Midlands Cancer Intelligence Unit Breast Cancer Registry and Edinburgh data sets); and economic modelling using the systematic reviews results, existing data sets, and focused searches for specific data analysis to determine the effectiveness and cost-utility of differing surveillance regimens. RESULTS: The majority of survey respondents initiate surveillance mammography 12 months after breast-conserving surgery (BCS) (87%) or mastectomy (79%). Annual surveillance mammography was most commonly reported for women after BCS or after mastectomy (72% and 53%, respectively). Most (74%) discharge women from surveillance mammography, most frequently 10 years after surgery. The majority (82%) discharge from clinical follow-up, most frequently at 5 years. Combining initiation, frequency and duration of surveillance mammography resulted in 54 differing surveillance regimens for women after BCS and 56 for women following mastectomy. The eight studies included in the clinical effectiveness systematic review suggest surveillance mammography offers a survival benefit compared with a surveillance regimen that does not include surveillance mammography. Nine studies were included in the test performance systematic review. For routine IBTR detection, surveillance mammography sensitivity ranged from 64% to 67% and specificity ranged from 85% to 97%. For magnetic resonance imaging (MRI), sensitivity ranged from 86% to 100% and specificity was 93%. For non-routine IBTR detection, sensitivity and specificity for surveillance mammography ranged from 50% to 83% and from 57% to 75%, respectively, and for MRI from 93% to 100% and from 88% to 96%, respectively. For routine MCBC detection, one study reported sensitivity of 67% and specificity of 50% for both surveillance mammography and MRI, although this was a highly select population. Data set analysis showed that IBTR has an adverse effect on survival. Furthermore, women experiencing a second tumour measuring >20 mm in diameter were at a significantly greater risk of death than those with no recurrence or those whose tumour was <10 mm in diameter. In the base-case analysis, the strategy with the highest net benefit, and most likely to be considered cost-effective, was surveillance mammography alone, provided every 12 months at a societal willingness to pay for a quality-adjusted life-year of either £20,000 or £30,000. The incremental cost-effectiveness ratio for surveillance mammography alone every 12 months compared with no surveillance was £4727. LIMITATIONS: Few studies met the review inclusion criteria and none of the studies was a randomised controlled trial. The limited and variable nature of the data available precluded any quantitative analysis. There was no useable evidence contained in the Breast Cancer Registry database to assess the effectiveness of surveillance mammography directly. The results of the economic model should be considered exploratory and interpreted with caution given the paucity of data available to inform the economic model. CONCLUSIONS: Surveillance is likely to improve survival and patients should gain maximum benefit through optimal use of resources, with those women with a greater likelihood of developing IBTR or MCBC being offered more comprehensive and more frequent surveillance. Further evidence is required to make a robust and informed judgement on the effectiveness of surveillance mammography and follow-up. The utility of national data sets could be improved and there is a need for high-quality, direct head-to-head studies comparing the diagnostic accuracy of tests used in the surveillance population. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Clinical effectiveness and cost-effectiveness of imatinib dose escalation for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours that have progressed on treatment at a dose of 400 mg/day: a systematic review and economic evaluation.

BACKGROUND: Imatinib dose escalation is advocated for gastrointestinal stromal tumour (GIST) treatment, but its effectiveness compared with sunitinib and best supportive care (BSC) after failure at the 400 mg/day dose is unknown. OBJECTIVES: To assess the effectiveness and cost-effectiveness of imatinib at escalated doses of 600 or 800 mg/day for patients with unresectable and/or metastatic GISTs whose disease had progressed on 400 mg/day. DATA SOURCES: Electronic databases, including MEDLlNE, MEDLINE In-Process, EMBASE, BIOSIS, Science Citation Index, Health Management Information Consortium and the Cochrane Controlled Trials Register, were searched until September 2009. REVIEW METHODS: A systematic review of the literature was carried out according to standard methods. An economic model was constructed to assess the cost-effectiveness of seven alternative pathways for treating patients with unresectable and/or metastatic GISTs. RESULTS: Five primary studies involving 669 people were included for clinical effectiveness; four reported imatinib and one reported sunitinib. The data were essentially observational as none of the studies was designed to specifically assess treatment of patients whose disease had progressed on 400 mg/day imatinib. For 600 mg/day imatinib, between 26% and 42% of patients showed either a partial response (PR) or stable disease (SD). Median time to progression was 1.7 months (range 0.7-24.9 months). For 800 mg/day imatinib, between 29% and 33% of patients showed either a PR or SD. Median overall survival (OS) was 19 months [95% confidence interval (CI) 13 to 23 months]. Progression-free survival ranged from 81 days to 5 months (95% CI 2 to 10 months). Median duration of response was 153 days (range 37-574 days). Treatment progression led to 88% discontinuations but between 16% and 31% of patients required a dose reduction, and 23% required a dose delay. There was a statistically significant increase in the severity of fatigue (p < 0.001) and anaemia (p = 0.015) following dose escalation. For sunitinib, median OS was 90 weeks (95% CI 73 to 106 weeks). For the cost-effectiveness review, only one full-text study and one abstract were identified, comparing imatinib at an escalated dose, sunitinib and BSC, although neither was based on a UK context. The definition of BSC was not consistent across the studies, and the pattern of resources (including drugs for treatment) and measures of effectiveness also varied. Within the model, BSC (assumed to include continuing medication to prevent tumour flare) was the least costly and least effective. It would be the care pathway most likely to be cost-effective when the cost per quality-adjusted life-year threshold was < £25,000. Imatinib at 600 mg/day was most likely to be cost-effective at a threshold between £25,000 and £45,000. Imatinib at 600 mg/day followed by further escalation followed by sunitinib was most likely to be cost-effective at a threshold > £45,000. LIMITATIONS: The evidence base was sparse, data were non-randomised and potentially biased. The economic model results are surrounded by a considerable degree of uncertainty and open to biases of unknown magnitude and direction. CONCLUSIONS: Around one-third of patients with unresectable and/or metastatic GIST, who fail on 400 mg/day of imatinib, may show response or SD with escalated doses. Between a threshold of £25,000 and £45,000, provision of an escalated dose of imatinib would be most likely to be cost-effective. However, these results should be interpreted with caution owing to the limited evidence available on outcomes following imatinib dose escalation or sunitinib for this group of patients. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Eltrombopag for the treatment of chronic idiopathic (immune) thrombocytopenic purpura (ITP).

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of eltrombopag for the treatment of adults with chronic idiopathic (immune) thrombocytopenic purpura (ITP), based on a review of the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. ITP is an autoimmune disorder by which antibodies are formed against platelets with annual incidence rates in the UK/USA ranging from 1.13 to 6.62 cases per 100,000 adults. Eltrombopag increases the production of platelets at a rate that outpaces their destruction by the immune system, and has a UK marketing authorisation both for the treatment of adult ITP in splenectomised patients who are refractory to other treatments and as a second-line treatment for adult non-splenectomised patients for whom surgery is contraindicated. Both splenectomised and non-splenectomised patient groups were considered in the analysis. Two economic models were presented, one for a watch-and-rescue treatment scenario and the second for the long-term treatment of patients with more severe ITP. The submission's evidence was sourced from the relatively high-quality RAISE [RAndomized placebo-controlled Idiopathic thrombocytopenic purpura (ITP) Study with Eltrombopag] randomised controlled trial. The study indicated a statistically significant difference in favour of eltrombopag compared with placebo in the odds of achieving the primary outcome of a platelet count of between 50 and 400 × 109/l during the 6-month treatment period (odds ratio 8.2, 99% confidence interval 3.6 to 18.7). In the eltrombopag group, 50/83 (60%) non-splenectomised patients and 18/49 (37%) splenectomised patients achieved this outcome. Median duration of response for all patients was 10.9 weeks (splenectomised patients 6 weeks and non-splenectomised patients 13.4 weeks). Patients treated with eltrombopag required less rescue medication and had lower odds of bleeding events than placebo-treated subjects in both patient groups. In the watch-and-rescue economic model, the ERG found that substantial reductions in the cost of eltrombopag are needed for the incremental cost-effectiveness ratio (ICER) to fall below £ 30,000. Further analyses found that the ICER varied from £33,561 to £ 103,500 per quality-adjusted life-year (QALY) (splenectomised) and from £ 39,657 to £ 150,245 per QALY (non-splenectomised). Other than bleeding, no adverse events were modelled. In relation to the long-term treatment model, the ERG found that using non-randomised non-comparative data may result in biased estimates of unknown magnitude and direction. None of the treatment sequences resulted in an ICER approaching the recommended threshold of £ 30,000. The base-case results, using a 2-year time horizon and prescribing eltrombopag as second-line treatment post rituximab, were found to be favourable towards eltrombopag. In conclusion, based on the MS and additional ERG work, eltrombopag appears to be a safe treatment for ITP (although long-term follow-up studies are awaited) and has short-term efficacy. However, there is no robust evidence on long-term efficacy or cost-effectiveness of eltrombopag, and there is a lack of robust direct evidence on the effectiveness and cost-effectiveness of eltrombopag compared with other relevant comparators. NICE did not recommend eltrombopag for the treatment of chronic ITP within its marketing authorisation for splenectomised or non-splenectomised patients.

Systematic review of the clinical effectiveness and cost-effectiveness of rapid point-of-care tests for the detection of genital chlamydia infection in women and men.

OBJECTIVE: To assess whether or not the Chlamydia Rapid Test (CRT) could improve detection of genital chlamydia, and whether it is more effective than current practice using nucleic acid amplification tests (NAATs), in terms of the number of cases of chlamydia that are detected and treated and the proportion of partners identified and treated. DATA SOURCES: Eleven electronic bibliographic databases (including MEDLINE and EMBASE) were searched until November 2008, as well as relevant websites. REVIEW METHODS: Studies of sexually active adolescent and adult women and men suspected of having or being tested for genital chlamydia infection were considered. The tests considered were the CRT and other comparator point-of-care tests identified, using a NAAT as a reference standard. Summary sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratios for each model were reported as a median and a 95% confidence interval (CI). Effectiveness was measured in terms of the absolute numbers of true-positives, false-positives, false-negatives (and other positive cases missed) and true-negatives detected. Costs were considered from the health service's perspective. Incremental cost-effectiveness ratios were used to examine the relative cost-effectiveness, and values of the major parameters of the models were varied in a sensitivity analysis. RESULTS: Thirteen studies enrolling 8817 participants were included in the analysis. In the pooled estimates for the CRT, sensitivity (95% CI) was 80% (73% to 85%) for vaginal swab specimens and 77% (59% to 89%) for first void urine (FVU) specimens. Specificity was 99% (99% to 100%) for vaginal swab specimens and 99% (98% to 99%) for FVU specimens. In the pooled estimates for a comparator point-of-care test (Clearview Chlamydia), sensitivity (95% CI) was 52% (39% to 65%) for vaginal, cervical and urethral swab specimens combined, and 64% (47% to 77%) for cervical specimens alone. Specificity was 97% (94% to 100%) for vaginal, cervical and urethral swab specimens combined, and 97% (88% to 99%) for cervical specimens alone. The results of the economic evaluation showed that for a hypothetical cohort of 1000 people, using the current practice of polymerase chain reaction testing would result in 12.63 people who were offered testing being correctly treated and having their sexual partners contacted, at a cost of 7070 pounds (for the whole cohort). For the CRT, the number being correctly treated would be 10.98, at a cost of 7180 pounds. For the Clearview Chlamydia test, the number correctly treated would be 7.14, at a cost of 7170 pounds. Both point-of-care tests were therefore more costly and less effective than current practice. CONCLUSIONS: The limited evidence available suggests that NAATs are still the most accurate and cost-effective method for diagnosing chlamydia infection. There may be circumstances in which point-of-care tests could be provided in addition to existing NAAT services, but there is currently little evidence on point-of-care methods in such settings. Robust evidence of the diagnostic accuracy of point-of-care tests for different types of samples is also still required, as are studies evaluating clinical effectiveness outcomes for these tests in comparison with NAATs.

Systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer.

OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of photodynamic diagnosis (PDD) compared with white light cystoscopy (WLC), and urine biomarkers [fluorescence in situ hybridisation (FISH), ImmunoCyt, NMP22] and cytology for the detection and follow-up of bladder cancer. DATA SOURCES: Major electronic databases including MEDLINE, MEDLINE In-Process, EMBASE, BIOSIS, Science Citation Index, Health Management Information Consortium and the Cochrane Controlled Trials Register were searched until April 2008. REVIEW METHODS: A systematic review of the literature was carried out according to standard methods. An economic model was constructed to assess the cost-effectiveness of alternative diagnostic and follow-up strategies for the diagnosis and management of patients with bladder cancer. RESULTS: In total, 27 studies reported PDD test performance. In pooled estimates [95% confidence interval (CI)] for patient-level analysis, PDD had higher sensitivity than WLC [92% (80% to 100%) versus 71% (49% to 93%)] but lower specificity [57% (36% to 79%) versus 72% (47% to 96%)]. Similar results were found for biopsy-level analysis. The median sensitivities (range) of PDD and WLC for detecting lower risk, less aggressive tumours were similar for patient-level detection [92% (20% to 95%) versus 95% (8% to 100%)], but sensitivity was higher for PDD than for WLC for biopsy-level detection [96% (88% to 100%) versus 88% (74% to 100%)]. For more aggressive, higher-risk tumours the median sensitivity of PDD for both patient-level [89% (6% to 100%)] and biopsy-level [99% (54% to 100%)] detection was higher than those of WLC [56% (0% to 100%) and 67% (0% to 100%) respectively]. Four RCTs comparing PDD with WLC reported effectiveness outcomes. PDD use at transurethral resection of bladder tumour resulted in fewer residual tumours at check cystoscopy [relative risk, RR, 0.37 (95% CI 0.20 to 0.69)] and longer recurrence-free survival [RR 1.37 (95% CI 1.18 to 1.59)] compared with WLC. In 71 studies reporting the performance of biomarkers and cytology in detecting bladder cancer, sensitivity (95% CI) was highest for ImmunoCyt [84% (77% to 91%)] and lowest for cytology [44% (38% to 51%)], whereas specificity was highest for cytology [96% (94% to 98%)] and lowest for ImmunoCyt [75% (68% to 83%)]. In the cost-effectiveness analysis the most effective strategy in terms of true positive cases (44) and life-years (11.66) [flexible cystoscopy (CSC) and ImmunoCyt followed by PDD in initial diagnosis and CSC followed by WLC in follow-up] had an incremental cost per life-year of over 270,000 pounds. The least effective strategy [cytology followed by WLC in initial diagnosis (average cost over 20 years 1403 pounds, average life expectancy 11.59)] was most likely to be considered cost-effective when society's willingness to pay was less than 20,000 pounds per life-year. No strategy was cost-effective more than 50% of the time, but four of the eight strategies in the probabilistic sensitivity analysis (three involving a biomarker or PDD) were each associated with a 20% chance of being considered cost-effective. In sensitivity analyses the results were most sensitive to the pretest probability of disease (5% in the base case). CONCLUSIONS: The advantages of PDD's higher sensitivity in detecting bladder cancer have to be weighed against the disadvantages of a higher false-positive rate. Taking into account the assumptions made in the model, strategies involving biomarkers and/or PDD provide additional benefits at a cost that society might be willing to pay. Strategies replacing WLC with PDD provide more life-years but it is unclear whether they are worth the extra cost.

Romiplostim for the treatment of chronic immune or idiopathic thrombocytopenic purpura: a single technology appraisal.

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of romiplostim for the treatment of adults with chronic immune or idiopathic thrombocytopenic purpura (ITP) based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submission's evidence came from two relatively high-quality randomised controlled trials (RCTs). The ERG found no evidence that any important data were missed or that data extraction was inaccurate. In both RCTs more patients in the romiplostim than in the placebo group achieved a durable platelet response [non-splenectomised patients: romiplostim 25/41 (61%), placebo 1/21 (5%), odds ratio (OR) 24.45, 95% confidence interval (CI) 3.34 to 179.18; splenectomised patients: romiplostim 16/42 (38%), placebo 0/21 (0%), OR 8.5 (95% CI 1.15 to 372)] and an overall platelet response [non-splenectomised patients: romiplostim 36/41 (88%), placebo 3/21 (14%), OR 34.74, 95% CI 7.77 to 155.38; splenectomised patients: romiplostim 33/42 (79%), placebo 0/21 (0%), OR 16.6 (95% CI 2.37 to 706]. The difference in mean period with a platelet response was 13.9 weeks (95% CI 10.5 to 17.4) in favour of romiplostim in the RCT of non-splectomised patients and 12.1 weeks (95% CI 8.7 to 15.6) in favour of romiplostim in the RCT of splectomised patients. The manufacturer's economic model evaluated the cost-effectiveness of romiplostim compared with standard care. The ERG had concerns about the way the decision problem was addressed in the economic model and about the non-adjustment of findings for confounding factors. In non-splenectomised patients, using romiplostim as a first option treatment, the base-case incremental cost-effectiveness ratio (ICER) was 14,840 pounds per quality-adjusted life-year (QALY). In splenectomised patients the ICER was 14,655 pounds per QALY. Additional sensitivity analyses performed by the ERG identified two issues of importance: whether individuals entered the model on watch and rescue or on active therapy in the comparator arm (ICER 21,674 pounds per QALY for non-splenectomised patients, 29,771 pounds per QALY for splenectomised patients); whether it was assumed that any unused medicine would be wasted. Combining all of the separate sensitivity analyses, and assuming that watch and rescue was not the first-line treatment, increased the ICERs further (non-splenectomised 37,290 pounds per QALY; splenectomised 131,017 pounds per QALY). In conclusion, the manufacturer's submission and additional work conducted by the ERG suggest that romiplostim has short-term efficacy for the treatment of ITP, but there is no robust evidence on long-term effectiveness or cost-effectiveness of romiplostim compared with relevant comparators.

Systematic review of the clinical effectiveness and cost-effectiveness of oesophageal Doppler monitoring in critically ill and high-risk surgical patients.

OBJECTIVES: To assess the effectiveness and cost-effectiveness of oesophageal Doppler monitoring (ODM) compared with conventional clinical assessment and other methods of monitoring cardiovascular function. DATA SOURCES: Electronic databases and relevant websites from 1990 to May 2007 were searched. REVIEW METHODS: This review was based on a systematic review conducted by the US Agency for Healthcare Research and Quality (AHRQ), supplemented by evidence from any additional studies identified. Comparator interventions for effectiveness were standard care, pulmonary artery catheters (PACs), pulse contour analysis monitoring and lithium or thermodilution cardiac monitoring. Data were extracted on mortality, length of stay overall and in critical care, complications and quality of life. The economic assessment evaluated strategies involving ODM compared with standard care, PACs, pulse contour analysis monitoring and lithium or thermodilution cardiac monitoring. RESULTS: The AHRQ report contained eight RCTs and was judged to be of high quality overall. Four comparisons were reported: ODM plus central venous pressure (CVP) monitoring plus conventional assessment vs CVP monitoring plus conventional assessment during surgery; ODM plus conventional assessment vs CVP monitoring plus conventional assessment during surgery; ODM plus conventional assessment vs conventional assessment during surgery; and ODM plus CVP monitoring plus conventional assessment vs CVP monitoring plus conventional assessment postoperatively. Five studies compared ODM plus CVP monitoring plus conventional assessment with CVP monitoring plus conventional assessment during surgery. There were fewer deaths [Peto odds ratio (OR) 0.13, 95% CI 0.02-0.96], fewer major complications (Peto OR 0.12, 95% CI 0.04-0.31), fewer total complications (fixed-effects OR 0.43, 95% CI 0.26-0.71) and shorter length of stay (pooled estimate not presented, 95% CI -2.21 to -0.57) in the ODM group. The results of the meta-analysis of mortality should be treated with caution owing to the low number of events and low overall number of patients in the combined totals. Three studies compared ODM plus conventional assessment with conventional assessment during surgery. There was no evidence of a difference in mortality (fixed-effects OR 0.81, 95% CI 0.23-2.77). Length of hospital stay was shorter in all three studies in the ODM group. Two studies compared ODM plus CVP monitoring plus conventional assessment vs CVP monitoring plus conventional assessment in critically ill patients. The patient groups were quite different (cardiac surgery and major trauma) and neither study, nor a meta-analysis, showed a statistically significant difference in mortality (fixed-effects OR 0.84, 95% CI 0.41-1.70). Fewer patients in the ODM group experienced complications (OR 0.49, 95% CI 0.30-0.81) and both studies reported a statistically significant shorter median length of hospital stay in that group. No economic evaluations that met the inclusion criteria were identified from the existing literature so a series of balance sheets was constructed. The results show that ODM strategies are likely to be cost-effective. CONCLUSIONS: More formal economic evaluation would allow better use of the available data. All identified studies were conducted in unconscious patients. However, further research is needed to evaluate new ODM probes that may be tolerated by awake patients. Given the paucity of the existing economic evidence base, any further primary research should include an economic evaluation or should provide data suitable for use in an economic model.

Systematic review and economic modelling of effectiveness and cost utility of surgical treatments for men with benign prostatic enlargement.

OBJECTIVES: To determine the clinical effectiveness and cost utility of procedures alternative to TURP (transurethral resection of the prostate) for benign prostatic enlargement (BPE) unresponsive to expectant, non-surgical treatments. DATA SOURCES: Electronic searches of 13 databases to identify relevant randomised controlled trials (RCTs). REVIEW METHODS: Two reviewers independently assessed study quality and extracted data. The International Prostate Symptom Score/American Urological Association (IPSS/AUA) symptom score was the primary outcome; others included quality of life, peak urine flow rate and adverse effects. Cost-effectiveness was assessed using a Markov model reflecting likely care pathways. RESULTS: 156 reports describing 88 RCTs were included. Most had fewer than 100 participants (range 12-234). TURP provided consistent, high-level, long-term symptomatic improvement. Minimally invasive procedures resulted in less marked improvement. Ablative procedures gave improvements equivalent to TURP. Holmium laser enucleation of the prostate (HoLEP) additionally resulted in greater improvement in flow rate. HoLEP is unique amongst the newer technologies in offering an advantage in urodynamic outcomes over TURP, although long-term follow-up data are lacking. Severe blood loss was more common following TURP. Rates of incontinence were similar across all interventions other than transurethral needle ablation (TUNA) and laser coagulation, for which lower rates were reported. Acute retention and reoperation were commoner with newer technologies, especially minimally invasive interventions. The economic model suggested that minimally invasive procedures were unlikely to be cost-effective compared with TURP. Transurethral vaporisation of the prostate (TUVP) was both less costly and less effective than TURP. HoLEP was estimated to be more cost-effective than a single TURP but less effective than a strategy involving repeat TURP if necessary. The base-case analysis suggested an 80% chance that TUVP, followed by HoLEP if required, would be cost-effective at a threshold of 20,000 pounds per quality-adjusted life-year. At a 50,000 pounds threshold, TUVP, followed by TURP as required, would be cost-effective, although considerable uncertainty surrounds this finding. The main limitations are the quantity and quality of the data available, in the context of multiple comparisons. CONCLUSIONS: In the absence of strong evidence in favour of newer methods, the standard--TURP--remains both clinically effective and cost-effective. There is a need for further research to establish (i) how many years of medical treatment are necessary to offset the cost of treatment with a minimally invasive or ablative intervention; (ii) more cost-effective alternatives to TURP; and (iii) strategies to improve outcomes after TURP.

Efficacy and safety of using mesh or grafts in surgery for anterior and/or posterior vaginal wall prolapse: systematic review and meta-analysis.

BACKGROUND: The efficacy and safety of mesh/graft in surgery for anterior or posterior pelvic organ prolapse is uncertain. OBJECTIVES: To systematically review the efficacy and safety of mesh/graft for anterior or posterior vaginal wall prolapse surgery. SEARCH STRATEGY: Electronic databases and conference proceedings were searched, experts and manufacturers contacted, and reference lists of retrieved papers scanned. SELECTION CRITERIA: Randomised controlled trials (RCTs), nonrandomised comparative studies, registries, case series involving at least 50 women, and RCTs published as conference abstracts from 2005 onwards. DATA COLLECTION AND ANALYSIS: One reviewer screened titles/abstracts, undertook data extraction, and assessed study quality. Data analysis was conducted for three subgroups: anterior, posterior, and anterior and/or posterior repair (not reported separately). RESULTS: Forty-nine studies involving 4569 women treated with mesh/graft were included. Study quality was generally high. Median follow up was 13 months (range 1-51 months). In anterior repair, there was short-term evidence that mesh/graft (any type) significantly reduced objective prolapse recurrence rates compared with no mesh/graft (relative risk 0.48, 95% CI 0.32-0.72). Nonabsorbable synthetic mesh had a significantly lower objective prolapse recurrence rate (8.8%, 48/548) than absorbable synthetic mesh (23.1%, 63/273) and biological graft (17.9%, 186/1041), but a higher erosion rate (10.2%, 68/666) than absorbable synthetic mesh (0.7%, 1/147) and biological graft (6.0%, 35/581). There was insufficient information to compare any of the other outcomes regardless of prolapse type. CONCLUSIONS: Evidence for most outcomes was too sparse to provide meaningful conclusions. Rigorous long-term RCTs are required to determine the comparative efficacy of using mesh/graft.

64-Slice computed tomography angiography in the diagnosis and assessment of coronary artery disease: systematic review and meta-analysis.

CONTEXT: Coronary artery disease (CAD) is a major cause of mortality and ill health. OBJECTIVE: To assess whether 64-slice CT angiography might replace some coronary angiography (CA) for diagnosis and assessment of CAD. DATA SOURCES: Electronic databases, conference proceedings and reference lists of included studies. STUDY SELECTION: Eligible studies compared 64-slice CT with a reference standard of CA in adults with suspected/known CAD, reporting sensitivity and specificity or true and false positives and negatives. DATA EXTRACTION: Two reviewers independently extracted data from included studies. RESULTS: Forty studies were included; 28 provided sufficient data for inclusion in the meta-analyses, all using a cut off point of >/=50% stenosis to define significant CAD. In patient-based detection (n = 1286) 64-slice CT pooled sensitivity was 99% (95% credible interval (CrI) 97% to 99%), specificity 89% (95% CrI 83% to 94%), median positive predictive value (PPV) across studies 93% (range 64-100%) and negative predictive value (NPV) 100% (range 86-100%). In segment-based detection (n = 14 199) 64-slice CT pooled sensitivity was 90% (95% CrI 85% to 94%), specificity 97% (95% CrI 95% to 98%), median PPV across studies 76% (range 44-93%) and NPV 99% (range 95-100%). CONCLUSIONS: 64-Slice CT is highly sensitive for patient-based detection of CAD and has high NPV. An ability to rule out significant CAD means that it may have a role in the assessment of chest pain, particularly when the diagnosis remains uncertain despite clinical evaluation and simple non-invasive testing.

Systematic review of the clinical effectiveness and cost-effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of coronary artery disease.

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness, in different patient groups, of the use of 64-slice or higher computed tomography (CT) angiography, instead of invasive coronary angiography (CA), for diagnosing people with suspected coronary artery disease (CAD) and assessing people with known CAD. DATA SOURCES: Electronic databases were searched from 2002 to December 2006. REVIEW METHODS: Included studies were tabulated and sensitivity, specificity, positive and negative predictive values calculated. Meta-analysis models were fitted using hierarchical summary receiver operating characteristic curves. Summary sensitivity, specificity, positive and negative likelihood ratios and diagnostic odds ratios for each model were reported as a median and 95% credible interval (CrI). Searches were also carried out for studies on the cost-effectiveness of 64-slice CT in the assessment of CAD. RESULTS: The diagnostic accuracy and prognostic studies enrolled over 2500 and 1700 people, respectively. The overall quality of the studies was reasonably good. In the pooled estimates, 64-slice CT angiography was highly sensitive (99%, 95% CrI 97 to 99%) for patient-based detection of significant CAD (defined as 50% or more stenosis), while across studies the negative predictive value (NPV) was very high (median 100%, range 86 to 100%). In segment-level analysis compared with patient-based detection, sensitivity was lower (90%, 95% CrI 85 to 94%, versus 99%, 95% CrI 97 to 99%) and specificity higher (97%, 95% CrI 95 to 98%, versus 89%, 95% CrI 83 to 94%), while across studies the median NPV was similar (99%, range 95 to 100%, versus 100%, range 86 to 100%). At individual coronary artery level the pooled estimates for sensitivity ranged from 85% for the left circumflex (LCX) artery to 95% for the left main artery, specificity ranged from 96% for both the left anterior descending (LAD) artery and LCX to 100% for the left main artery, while across studies the positive predictive value (PPV) ranged from 81% for the LCX to 100% for the left main artery and NPV was very high, ranging from 98% for the LAD (range 95 to 100%), LCX (range 93 to 100%) and right coronary artery (RCA) (range 94 to 100%) to 100% for the left main artery. The pooled estimates for bypass graft analysis were 99% (95% CrI 95 to 100%) sensitivity, 96% (95% CrI 86 to 99%) specificity, with median PPV and NPV values across studies of 93% (range 90 to 95%) and 99% (range 98 to 100%), respectively. This compares with, for stent analysis, a pooled sensitivity of 89% (95% CrI 68 to 97%), specificity 94% (95% CrI 83 to 98%), and median PPV and NPV values across studies of 77% (range 33 to 100%) and 96% (range 71 to 100%), respectively. Sixty-four-slice CT is almost as good as invasive CA in terms of detecting true positives. However, it is somewhat poorer in its rate of false positives. It seems likely that diagnostic strategies involving 64-slice CT will still require invasive CA for CT test positives, partly to identify CT false positives, but also because CA provides other information that CT currently does not, notably details of insertion site and distal run-off for possible coronary artery bypass graft (CABG). The high sensitivity of 64-slice CT avoids the costs of unnecessary CA in those referred for investigation but who do not have CAD. Given the possible, although small, associated death rate, avoiding these unnecessary CAs through the use of 64-slice CT may also confer a small immediate survival advantage. This in itself may be sufficient to outweigh the very marginally inferior rates of detection of true positives by strategies involving 64-slice CT. The avoidance of unnecessary CA through the use of 64-slice CT also appears likely to result in overall cost savings in the diagnostic pathway. Only if both the cost of CA is relatively low and the prevalence of CAD in the presenting population is relatively high (so that most patients will go on to CA) will the use of 64-slice CT be likely to result in a higher overall diagnostic cost per patient. CONCLUSIONS: The main value of 64-slice CT may at present be to rule out significant CAD. It is unlikely to replace CA in assessment for revascularisation of patients, particularly as angiography and angioplasty are often done on the same occasion. Further research is needed into the marginal advantages and costs of 256-slice machines compared with 64-slice CT, the usefulness of 64-slice CT in people with suspected acute coronary syndrome, the potential of multislice computed tomography to examine plaque morphology, the role of CT in identifying patients suitable for CABG, and the concerns raised about repetitive use, or use of 64-slice or higher CT angiography in younger individuals or women of childbearing age.

Sacral nerve stimulation for fecal incontinence and constipation in adults: a short version Cochrane review.

BACKGROUND: Fecal incontinence and constipation are disabling conditions that reduce quality of life. If conservative treatment fails, one option is sacral nerve stimulation (SNS), a minimally invasive technique allowing modulation of the nerves and muscles of the pelvic floor and hindgut. OBJECTIVES: To assess the effects of SNS for fecal incontinence and constipation in adults. SEARCH STRATEGY: We searched the Cochrane Incontinence Group Specialized Trials Register (searched 24 April 2007) and the reference lists of relevant articles. SELECTION CRITERIA: All randomized or quasi-randomized trials assessing the effects of SNS for fecal incontinence or constipation in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, assessed the methodological quality of the included studies, and undertook data extraction. MAIN RESULTS: Three crossover studies were included. Two, enrolling 34 (Leroi) and two participants (Vaizey), assessed the effects of SNS for fecal incontinence, and one (Kenefick), enrolling two participants, assessed SNS for constipation. In the study by Leroi, following the crossover period, participants, while still blinded, chose the period of stimulation they had preferred. Outcomes at different time points were reported separately for 19 participants who preferred the "on" and five who preferred the "off" period. For the group of 19, the median (range) episodes of fecal incontinence per week fell from 1.7 (0-9) during the "off" period to 0.7 (0-5) during the "on" period; for the group of five, however, the median (range) rose from 1.7 (0-11) during the "off" period compared with 3.7 (0-11) during the "on" period. Vaizey reported an average of six, and one, episodes of fecal incontinence per week during the "off" and "on" periods, respectively. Leroi reported that four of 27 participants experienced an adverse event resulting in removal of the stimulator; Vaizey did not report adverse events. For SNS for constipation, during the "off" crossover period the participants experienced an average of two bowel movements per week, compared with five during the "on" period. Abdominal pain and bloating occurred 79% of the time during the "off" period compared with 33% during the "on" period. No adverse events occurred. AUTHORS' CONCLUSIONS: The very limited evidence from the included studies suggests that SNS can improve continence in selected people with fecal incontinence, and reduce symptoms in selected people with constipation. However, temporary, percutaneous stimulation for a 2-3-week period does not always successfully identify those for whom a permanent implant will be beneficial. Larger, good quality randomized crossover trials are needed to allow the effects of SNS for these conditions to be assessed with more certainty.

The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematic review and economic evaluation.

OBJECTIVES: To assess whether open angle glaucoma (OAG) screening meets the UK National Screening Committee criteria, to compare screening strategies with case finding, to estimate test parameters, to model estimates of cost and cost-effectiveness, and to identify areas for future research. DATA SOURCES: Major electronic databases were searched up to December 2005. REVIEW METHODS: Screening strategies were developed by wide consultation. Markov submodels were developed to represent screening strategies. Parameter estimates were determined by systematic reviews of epidemiology, economic evaluations of screening, and effectiveness (test accuracy, screening and treatment). Tailored highly sensitive electronic searches were undertaken. RESULTS: Most potential screening tests reviewed had an estimated specificity of 85% or higher. No test was clearly most accurate, with only a few, heterogeneous studies for each test. No randomised controlled trials (RCTs) of screening were identified. Based on two treatment RCTs, early treatment reduces the risk of progression. Extrapolating from this, and assuming accelerated progression with advancing disease severity, without treatment the mean time to blindness in at least one eye was approximately 23 years, compared to 35 years with treatment. Prevalence would have to be about 3-4% in 40 year olds with a screening interval of 10 years to approach cost-effectiveness. It is predicted that screening might be cost-effective in a 50-year-old cohort at a prevalence of 4% with a 10-year screening interval. General population screening at any age, thus, appears not to be cost-effective. Selective screening of groups with higher prevalence (family history, black ethnicity) might be worthwhile, although this would only cover 6% of the population. Extension to include other at-risk cohorts (e.g. myopia and diabetes) would include 37% of the general population, but the prevalence is then too low for screening to be considered cost-effective. Screening using a test with initial automated classification followed by assessment by a specialised optometrist, for test positives, was more cost-effective than initial specialised optometric assessment. The cost-effectiveness of the screening programme was highly sensitive to the perspective on costs (NHS or societal). In the base-case model, the NHS costs of visual impairment were estimated as 669 pounds. If annual societal costs were 8800 pounds, then screening might be considered cost-effective for a 40-year-old cohort with 1% OAG prevalence assuming a willingness to pay of 30,000 pounds per quality-adjusted life-year. Of lesser importance were changes to estimates of attendance for sight tests, incidence of OAG, rate of progression and utility values for each stage of OAG severity. Cost-effectiveness was not particularly sensitive to the accuracy of screening tests within the ranges observed. However, a highly specific test is required to reduce large numbers of false-positive referrals. The findings that population screening is unlikely to be cost-effective are based on an economic model whose parameter estimates have considerable uncertainty. In particular, if rate of progression and/or costs of visual impairment are higher than estimated then screening could be cost-effective. CONCLUSIONS: While population screening is not cost-effective, the targeted screening of high-risk groups may be. Procedures for identifying those at risk, for quality assuring the programme, as well as adequate service provision for those screened positive would all be needed. Glaucoma detection can be improved by increasing attendance for eye examination, and improving the performance of current testing by either refining practice or adding in a technology-based first assessment, the latter being the more cost-effective option. This has implications for any future organisational changes in community eye-care services. Further research should aim to develop and provide quality data to populate the economic model, by conducting a feasibility study of interventions to improve detection, by obtaining further data on costs of blindness, risk of progression and health outcomes, and by conducting an RCT of interventions to improve the uptake of glaucoma testing.

Systematic review of foam sclerotherapy for varicose veins.

BACKGROUND AND METHOD: Foam sclerotherapy is a potential treatment for varicose veins. A systematic review was undertaken to assess its safety and efficacy. RESULTS: Sixty-nine studies were included. The median rates of serious adverse events, including pulmonary embolism and deep vein thrombosis, were less than 1 per cent. The median rate of visual disturbance was 1.4 per cent, headache 4.2 per cent, thrombophlebitis 4.7 per cent, matting/skin staining/pigmentation 17.8 per cent and pain at the site of injection 25.6 per cent. The median rate of complete occlusion of treated veins was 87.0 per cent and for recurrence or development of new veins it was 8.1 per cent. Meta-analysis for complete occlusion suggests that foam sclerotherapy is less effective than surgery (relative risk (RR) 0.86 (95 per cent confidence interval (c.i.) 0.67 to 1.10)) but more effective than liquid sclerotherapy (RR 1.39 (95 per cent c.i. 0.91 to 2.11)), although there was substantial heterogeneity between studies. CONCLUSION: Serious adverse events associated with foam sclerotherapy are rare. There is insufficient evidence to allow a meaningful comparison of the effectiveness of this treatment with that of other minimally invasive therapies or surgery.

Sacral nerve stimulation for faecal incontinence and constipation in adults.

BACKGROUND: Faecal incontinence and constipation are disabling conditions that reduce quality of life. If conservative treatment fails, one option is sacral nerve stimulation (SNS), a minimally invasive technique allowing modulation of the nerves and muscles of the pelvic floor and hindgut. OBJECTIVES: To assess the effects of SNS for faecal incontinence and constipation in adults. SEARCH STRATEGY: We searched the Cochrane Incontinence Group Specialised Trials Register (searched 24 April 2007) and the reference lists of relevant articles. SELECTION CRITERIA: All randomised or quasi-randomised trials assessing the effects of SNS for faecal incontinence or constipation in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, assessed the methodological quality of the included studies, and undertook data extraction. MAIN RESULTS: Three crossover studies were included. Two, enrolling 34 (Leroi) and two participants (Vaizey), assessed the effects of SNS for faecal incontinence, and one (Kenefick), enrolling two participants, assessed SNS for constipation. In the study by Leroi, following the crossover period, participants, while still blinded, chose the period of stimulation they had preferred. Outcomes at different time points were reported separately for 19 participants who preferred the 'on' and five who preferred the 'off' period. For the group of 19, the median (range) episodes of faecal incontinence per week fell from 1.7 (0 to 9) during the 'off' period to 0.7 (0 to 5) during the 'on' period; for the group of five, however, the median (range) rose from 1.7 (0 to 11) during the 'off' period compared with 3.7 (0 to 11) during the 'on' period. Vaizey reported an average of six, and one, episodes of faecal incontinence per week during the 'off' and 'on' periods respectively. Leroi reported that four of 27 participants experienced an adverse event resulting in removal of the stimulator; Vaizey did not report adverse events. For SNS for constipation, during the 'off' crossover period the participants experienced an average of two bowel movements per week, compared with five during the 'on' period. Abdominal pain and bloating occurred 79% of the time during the 'off' period compared with 33% during the 'on' period. No adverse events occurred. AUTHORS' CONCLUSIONS: The very limited evidence from the included studies suggests that SNS can improve continence in selected people with faecal incontinence, and reduce symptoms in selected people with constipation. However temporary, percutaneous stimulation for a two-to-three week period does not always successfully identify those for whom a permanent implant will be beneficial. Larger, good quality randomised crossover trials are needed to allow the effects of SNS for these conditions to be assessed with more certainty.