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Background Chronic kidney disease–associated pruritus (CKD-aP) is a common and burdensome condition for end-stage kidney disease (ESKD) patients, especially those receiving haemodialysis. High-quality evidence of the relationship between CKD-aP and health-related quality of life (HRQoL) can therefore inform clinicians and policymakers about treatment choice and reimbursement decisions. Methods A systematic literature review and narrative synthesis stratified by study design and HRQoL instrument was conducted to evaluate in adult ESKD patients receiving in-centre haemodialysis the relationship between CKD-aP and HRQoL assessed using multi dimensional generic or condition-specific preference- or non-preference-based measures. MEDLINE, Embase, Web of Science, BIOSIS Citation Index, Cochrane Library and PsycINFO from inception to March 2020 were searched, with two reviewers extracting data independently. Results Searches identified 2684 unique records, of which 20 papers relating to 18 unique studies [5 randomised controlled trials (RCTs) and 13 observational studies] were included. HRQoL was assessed using four generic and eight disease-specific measures. The impact of CKD-aP was assessed by comparison of means, linear regression and correlation. Observational studies employing comprehensively adjusted multivariable linear regression largely found associations between CKD-aP severities and HRQoL. Analyses suggest this relationship is partially mediated by the sleep disturbance caused by CKD-aP. RCTs showing improvements in CKD-aP severity were associated with clinically meaningful improvements in HRQoL. Compared with generic measures, disease-specific HRQoL instruments reported greater changes with reduced CKD-aP. Heterogeneity in study design and reporting precluded meta-analysis. Conclusions CKD-aP severity was found to be associated with a worsening of HRQoL in the majority of observational and RCT studies. Parallel improvements in CKD-aP and HRQoL with interventions may support their use (PROSPERO registration 175035).

Background Antimicrobial resistance (AMR) causes substantial health and economic burden to individuals, healthcare systems and societies globally. Understanding the temporal relationship between antibiotic consumption and antibiotic resistance in hospitalized patients can better inform antibiotic stewardship activities and the time frame for their evaluation. Objectives This systematic review examined the temporal relationship between antibiotic use and development of antibiotic resistance for 42 pre-defined antibiotic and pathogen combinations in hospitalized adults in Europe. Methods Searches in MEDLINE, Embase, Cochrane Library and NIHR Centre for Reviews and Dissemination were undertaken from 2000 to August 2021. Pathogens of interest were Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus, Enterococcus faecium, CoNS, Pseudomonas aeruginosa and Acinetobacter baumannii complex. Results Twenty-eight ecological studies and one individual-level study were included. Ecological studies were predominantly retrospective in design (19 studies) and of reasonable (20 studies) to high (8 studies) methodological quality. Of the eight pathogens of interest, no relevant data were identified for S. pneumoniae and CoNS. Across all pathogens, the time-lag data from the 28 ecological studies showed a similar pattern, with the majority of studies reporting lags ranging from 0 to 6 months. Conclusions Development of antibiotic resistance for the investigated antibiotic/pathogen combinations tends to occur over 0 to 6 months following exposure within European hospitals. This information could inform planning of antibiotic stewardship activities in hospital settings.

Background We aimed to assess the cost effectiveness of intravitreal ranibizumab (Lucentis), aflibercept (Eylea) and bevacizumab (Avastin) for the treatment of macular oedema due to central retinal vein occlusion. Methods We calculated costs and quality-adjusted life-years from the UK National Health Service and Personal Social Services perspective. We performed a within-trial analysis using the efficacy, safety, resource use and health utility data from a randomised controlled trial (LEAVO) over 100 weeks. We built a discrete event simulation to model long-term outcomes. We estimated utilities using the Visual-Functioning Questionnaire-Utility Index, EQ-5D and EQ-5D with an additional vision question. We used standard UK costs sources for 2018/19 and a cost of £28 per bevacizumab injection. We discounted costs and quality-adjusted life-years at 3.5% annually. Results Bevacizumab was the least costly intervention followed by ranibizumab and aflibercept in both the within-trial analysis (bevacizumab: £6292, ranibizumab: £13,014, aflibercept: £14,328) and long-term model (bevacizumab: £18,353, ranibizumab: £30,226, aflibercept: £35,026). Although LEAVO did not demonstrate bevacizumab to be non-inferior for the visual acuity primary outcome, the three interventions generated similar quality-adjusted life-years in both analyses. Bevacizumab was always the most cost-effective intervention at a threshold of £30,000 per quality-adjusted life-year, even using the list price of £243 per injection. Conclusions Wider adoption of bevacizumab for the treatment of macular oedema due to central retinal vein occlusion could result in substantial savings to healthcare systems and deliver similar health-related quality of life. However, patients, funders and ophthalmologists should be fully aware that LEAVO could not demonstrate that bevacizumab is non-inferior to the licensed agents.

Objective\ud This review examined the psychometric performance of 4 generic child- and adolescent-specific preference-based measures that can be used to produce utilities for child and adolescent health.\ud \ud Methods\ud A systematic search was undertaken to identify studies reporting the psychometric performance of the Child Health Utility (CHU9D), EQ-5D-Y (3L or 5L), and Health Utilities Index Mark 2 (HUI2) or Mark 3 (HUI3) in children and/or adolescents. Data were extracted to assess known-group validity, convergent validity, responsiveness, reliability, acceptability, and feasibility. Data were extracted separately for the dimensions and utility index where this was reported.\ud \ud Results\ud The review included 76 studies (CHU9D n = 12, EQ-5D-Y-3L n = 20, HUI2 n = 26,HUI3 n = 43), which varied considerably across conditions and sample size. EQ-5D-Y-3L had the largest amount of evidence of good psychometric performance in proportion to the number of studies examining performance. The majority of the evidence related to EQ-5D-Y-3L was based on dimensions. CHU9D was assessed in fewer studies, but the majority of studies found evidence of good psychometric performance. Evidence for HUI2 and HUI3 was more mixed, but the studies were more limited in sample size and statistical power, which was likely to have affected performance.\ud \ud Conclusions\ud The heterogeneity of published studies means that the evidence is based on studies across a range of countries, populations and conditions, using different study designs, different languages, different value sets and different statistical techniques. Evidence for CHU9D in particular is based on a limited number of studies. The findings raise concerns about the comparability of self-report and proxy-report responses to generate utility values for children and adolescents.

Background: Surgical site infection is a serious complication associated with significant morbidity, mortality and health care expenditure. Aims: To determine the clinical effectiveness and economic impact of using iodine-impregnated incise drapes for preventing surgical site infection. Methods: MEDLINE, Embase, Cochrane Library and CINAHL databases were systematically searched. Critical appraisal and synthesis of clinical evidence informed a decision analytical cost-consequence model. Findings: Nine studies were included in the systematic literature review. Evidence from cardiac surgery patients was considered appropriate to inform the cost analysis. The economic model evaluation estimated cost savings of £549 per patient with the iodophor-impregnated drape in the deterministic analysis and a mean cost saving per patient of £554,172 per 1000 in the probabilistic analysis. Conclusion: Using iodine-impregnated drapes in cardiac surgery patients may effectively reduce infections and provide cost-savings, but further research is required.

Rationale & Objective Disordered mineral metabolism complicates chronic kidney disease (CKD), but the effect of reduced kidney function on fracture risk has not been fully established. We conducted a systematic review and meta-analysis of the risks for hip and nonvertebral fractures in people with CKD. We also investigated the effects of age, sex, and CKD stage. Study Design Systematic review and meta-analysis. Study Population Adults with CKD glomerular filtration rate (GFR) categories 3a-5D (G3a-G5D) compared with adults without CKD G3a-G5D. Selection Criteria for Studies Observational studies. Data Extraction Data extraction was conducted by 1 reviewer and checked by a second reviewer. Analytical Approach MEDLINE, EMBASE, and Cochrane databases were searched in March 2018 and an update was conducted in November 2019. We used random-effects models to calculate pooled risk estimates and 95% CIs. Results 17 studies met the inclusion criteria. We included 13 studies in the hip fracture systematic review and 10 studies in the meta-analysis. Studies reported data from 250,440,035 participants; 5,798,566 with CKD G3a-G5D and 363,410 with hip fractures. 4 studies were included in the nonvertebral fracture analysis, reporting data from 1,396,976 participants; 464,978 with CKD G3a-G5D and 115,284 fractures. Studies reported data from participants aged 18 to older than 90 years. We found a significant increase in fracture risk both for hip (relative risk [RR], 2.36; 95% CI, 1.64-3.39) and nonvertebral fractures (RR, 1.47; 95% CI, 1.15-1.88). For hip fractures, younger patients ( 65 years; RR, 2.11; 95% CI, 1.41-3.16). Greater GFR loss was associated with higher relative risk for fractures. Limitations We could not assess the effects of bone mineral density, biochemical abnormalities, renal osteodystrophy, frailty, falls, or medications on risk for fractures. Conclusions Risks for hip and nonvertebral fractures are increased in CKD G3a-G5D. The relative risk of hip fracture is greater in the younger than the older population and increases progressively with loss of GFR. We suggest that fracture prevention should be a consideration in CKD at any age.

Background Licensed ranibizumab (0.5 mg/0.05 ml Lucentis®; Novartis International AG, Basel, Switzerland) and aflibercept (2 mg/0.05 ml Eylea®; Bayer AG, Leverkusen, Germany) and unlicensed bevacizumab (1.25 mg/0.05 ml Avastin®; F. Hoffmann-La Roche AG, Basel, Switzerland) are used to treat macula oedema due to central retinal vein occlusion, but their relative clinical effectiveness, cost-effectiveness and impact on the UK NHS and Personal Social Services have never been directly compared over the typical disease treatment period. Objective The objective was to compare the clinical effectiveness and cost-effectiveness of three intravitreal antivascular endothelial growth factor agents for the management of macula oedema due to central retinal vein occlusion. Design This was a three-arm, double-masked, randomised controlled non-inferiority trial. Setting The trial was set in 44 UK NHS ophthalmology departments, between 2014 and 2018. Participants A total of 463 patients with visual impairment due to macula oedema secondary to central retinal vein occlusion were included in the trial. Interventions The participants were treated with repeated intravitreal injections of ranibizumab (n = 155), aflibercept (n = 154) or bevacizumab (n = 154). Main outcome measures The primary outcome was an increase in the best corrected visual acuity letter score from baseline to 100 weeks in the trial eye. The null hypothesis that aflibercept and bevacizumab are each inferior to ranibizumab was tested with a non-inferiority margin of –5 visual acuity letters over 100 weeks. Secondary outcomes included additional visual acuity, and imaging outcomes, Visual Function Questionnaire-25, EuroQol-5 Dimensions with and without a vision bolt-on, and drug side effects. Cost-effectiveness was estimated using treatment costs and Visual Function Questionnaire-Utility Index to measure quality-adjusted life-years. Results The adjusted mean changes at 100 weeks in the best corrected visual acuity letter scores were as follows – ranibizumab, 12.5 letters (standard deviation 21.1 letters); aflibercept, 15.1 letters (standard deviation 18.7 letters); and bevacizumab, 9.8 letters (standard deviation 21.4 letters). Aflibercept was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference 2.23 letters, 95% confidence interval –2.17 to 6.63 letters; p = 0.0006), but not superior. The study was unable to demonstrate that bevacizumab was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference –1.73 letters, 95% confidence interval –6.12 to 2.67 letters; p = 0.071). A post hoc analysis was unable to demonstrate that bevacizumab was non-inferior to aflibercept in the intention-to-treat population (adjusted mean best corrected visual acuity difference was –3.96 letters, 95% confidence interval –8.34 to 0.42 letters; p = 0.32). All per-protocol population results were the same. Fewer injections were required with aflibercept (10.0) than with ranibizumab (11.8) (difference in means –1.8, 95% confidence interval –2.9 to –0.8). A post hoc analysis showed that more bevacizumab than aflibercept injections were required (difference in means 1.6, 95% confidence interval 0.5 to 2.7). There were no new safety concerns. The model- and trial-based cost-effectiveness analyses estimated that bevacizumab was the most cost-effective treatment at a threshold of £20,000–30,000 per quality-adjusted life-year. Limitations The comparison of aflibercept and bevacizumab was a post hoc analysis. Conclusion The study showed aflibercept to be non-inferior to ranibizumab. However, the possibility that bevacizumab is worse than ranibizumab and aflibercept by 5 visual acuity letters cannot be ruled out. Bevacizumab is an economically attractive treatment alternative and would lead to substantial cost savings to the NHS and other health-care systems. However, uncertainty about its relative effectiveness should be discussed comprehensively with patients, their representatives and funders before treatment is considered. Future work To obtain extensive patient feedback and discuss with all stakeholders future bevacizumab NHS use. Trial registration Current Controlled Trials ISRCTN13623634. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 38. See the NIHR Journals Library website for further project information.

BackgroundVascular services is changing rapidly, having emerged as a new specialty with its own training and specialised techniques. This has resulted in the need for reconfiguration of services to provide adequate specialist provision and accessible and equitable services.ObjectivesTo identify the effects of service configuration on practice, resource use and outcomes. To model potential changes in configuration. To identify and/or develop electronic data collection tools for collecting patient-reported outcome measures and other clinical information. To evaluate patient preferences for aspects of services other than health-related quality of life.DesignThis was a multiple methods study comprising multiple systematic literature reviews; the development of a new outcome measure for users of vascular services (the electronic Personal Assessment Questionnaire – Vascular) based on the reviews, qualitative studies and psychometric evaluation; a trade-off exercise to measure process utilities; Hospital Episode Statistics analysis; and the development of individual disease models and a metamodel of service configuration.SettingSpecialist vascular inpatient services in England.Data sourcesModelling and Hospital Episode Statistics analysis for all vascular inpatients in England from 2006 to 2018. Qualitative studies and electronic Personal Assessment Questionnaire – Vascular evaluation with vascular patients from the Sheffield area. The trade-off studies were based on a societal sample from across England.InterventionsThe data analysis, preference studies and modelling explored the effect of different potential arrangements for service provision on the resource use, workload and outcomes for all interventions in the three main areas of inpatient vascular treatment: peripheral arterial disease, abdominal aortic aneurysm and carotid artery disease. The electronic Personal Assessment Questionnaire – Vascular was evaluated as a potential tool for clinical data collection and outcome monitoring.Main outcome measuresSystematic reviews assessed quality and psychometric properties of published outcome measures for vascular disease and the relationship between volume and outcome in vascular services. The electronic Personal Assessment Questionnaire – Vascular development considered face and construct validity, test–retest reliability and responsiveness. Models were validated using case studies from previous reconfigurations and comparisons with Hospital Episode Statistics data. Preference studies resulted in estimates of process utilities for aneurysm treatment and for travelling distances to access services.ResultsSystematic reviews provided evidence of an association between increasing volume of activity and improved outcomes for peripheral arterial disease, abdominal aortic aneurysm and carotid artery disease. Reviews of existing patient-reported outcome measures did not identify suitable condition-specific tools for incorporation in the electronic Personal Assessment Questionnaire – Vascular. Reviews of qualitative evidence, primary qualitative studies and a Delphi exercise identified the issues to be incorporated into the electronic Personal Assessment Questionnaire – Vascular, resulting in a questionnaire with one generic and three disease-specific domains. After initial item reduction, the final version has 55 items in eight scales and has acceptable psychometric properties. The preference studies showed strong preference for endovascular abdominal aortic aneurysm treatment (willingness to trade up to 0.135 quality-adjusted life-years) and for local services (up to 0.631 quality-adjusted life-years). A simulation model with a web-based interface was developed, incorporating disease-specific models for abdominal aortic aneurysm, peripheral arterial disease and carotid artery disease. This predicts the effects of specified reconfigurations on workload, resource use, outcomes and cost-effectiveness. Initial exploration suggested that further reconfiguration of services in England to accomplish high-volume centres would result in improved outcomes, within the bounds of cost-effectiveness usually considered acceptable in the NHS.LimitationsThe major source of evidence to populate the models was Hospital Episode Statistics data, which have limitations owing to the complexity of the data, deficiencies in the coding systems and variations in coding practice. The studies were not able to address all of the potential barriers to change where vascular services are not compliant with current NHS recommendations.ConclusionsThere is evidence of potential for improvement in the clinical effectiveness and cost-effectiveness of vascular services through further centralisation of sites where major vascular procedures are undertaken. Preferences for local services are strong, and this may be addressed through more integrated services, with a range of services being provided more locally. The use of a web-based tool for the collection of clinical data and patient-reported outcome measures is feasible and can provide outcome data for clinical use and service evaluation.Future workFurther evaluation of the economic models in real-world situations where local vascular service reconfiguration is under consideration and of the barriers to change where vascular services do not meet NHS recommendations for service configuration is needed. Further work on the electronic Personal Assessment Questionnaire – Vascular is required to assess its acceptability and usefulness in clinical practice and to develop appropriate report formats for clinical use and service evaluation. Further studies to assess the implications of including non-health-related preferences for care processes, and location of services, in calculations of cost-effectiveness are required.Study registrationThis study is registered as PROSPERO CRD42016042570, CRD42016042573, CRD42016042574, CRD42016042576, CRD42016042575, CRD42014014850, CRD42015023877 and CRD42015024820.FundingThis project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full inProgramme Grants for Applied Research; Vol. 9, No. 5. See the NIHR Journals Library website for further project information.

Background\ud Diabetes is associated with increased fracture risk but we do not know what affects this risk. We investigated the risk of hip and non-vertebral fractures in diabetes and whether this risk was affected by age, gender, body mass index, diabetes type and duration, insulin use and diabetic complications.\ud \ud Methods\ud We selected a previously published review to be updated. MEDLINE, Embase and Cochrane databases were searched up to March 2020. We included observational studies with age and gender-adjusted risk of fractures in adults with diabetes compared to adults without diabetes. We extracted data from published reports that we summarised using random effects model.\ud \ud Findings\ud From the 3140 records identified, 49 were included, 42 in the hip fracture analysis, reporting data from 17,571,738 participants with 319,652 fractures and 17 in the non-vertebral fracture review, reporting data from 2,978,487 participants with 181,228 fractures. We found an increase in the risk of fracture in diabetes both for hip (RR 4.93, 3.06–7.95, in type 1 diabetes and RR1.33, 1.19–1.49, in type 2 diabetes) and for non-vertebral fractures (RR 1.92, 0.92–3.99, in type 1 and RR 1.19, 1,11–1.28 in type 2). At the hip, the risk was higher in the younger population in both type 1 and type 2 diabetes. In those with type 2 diabetes, longer diabetes duration and insulin use was associated with an increased risk. We did not investigate the effect of bone density, falls, anti-diabetic drugs and hypoglycemia.\ud \ud Conclusion\ud Diabetes is associated with an increase in both hip and non-vertebral fracture risk.

Background Previous meta-analyses have reported an increase in the risk of hip fractures in diabetes, but the risk of non-vertebral fractures has not been investigated. In addition, it is not known how the risk of fractures is affected by age, body mass index, diabetes duration and insulin use. To investigate these features, we conducted a meta-analysis on the risk of hip and non-vertebral fractures in diabetes. MethodsWe selected a previously published review to be updated. Medline, Embase and Cochrane databases were searched in March 2018 and an update conducted in March 2019 (Pubmed) using relevant MeSH and free text terms such as “diabetes”, “hyperglycaemia” and “fracture”. We selected observational studies with data on the risk of fractures in adults ολδερ τηαν 18 years old with diabetes compared to people without diabetes. Study quality was assessed using the Newcastle Ottawa Scale. We used the random-effects model to calculate the risk estimates and 95% confidence intervals.Results Forty-nine studies were included. Forty-three studies were included in the hip fracture analysis, 40 cohorts and 3 case-control studies, reporting data from 17,575,873 participants, 2,387,899 with diabetes and 321,720 fractures. Eighteen studies reported the risk of fractures in two or more sites and were included in the non-vertebral fracture risk analysis. All but one study were cohorts. These studies reported data from 2,982,622 participants, 414,195 with diabetes and 185,363 fractures. In both analyses, age varies from 20 to 100 years old, including both type 1 and type 2 diabetes. Overall, the study quality was judged to be moderate to good.We found a significant increase in the risk of fracture in diabetes both for hip (RR 1.52, 95% CI 1.42-1.63) and for non-vertebral fracture (RR 1.20, 1.14-1.27). The increase in the risk was greater for insulin users and longer duration of diabetes, at both sites. At the hip, the risk was higher in the younger population, women, and those with T1D. ConclusionThere was an increase in the risk of hip and non-vertebral fractures in diabetes. Although the mechanisms are not established, patients with type 1 diabetes were the population at higher relative risk. The evidence suggest that the skeleton should be considered a site for diabetic complications.

This study evaluates the clinical and cost effectiveness of a 2-layer compression system (2LBA; 3M Coban Two-Layer Compression System; 3M, St Paul, MN) compared with other 2-layer (2LB) and 4-layer (4LB) compression systems in patients with noninfected venous leg ulcers (VLUs).The MEDLINE, EMBASE, CINAHL, Cochrane Library, National Health Service (NHS) Economic Evaluation, and EconLit databases were searched from inception up to January 2017. The MEDLINE search was updated on March 31, 2017. Study selection, quality assessment, and data synthesis were undertaken in accordance with recommended standards. Findings were presented narratively.In total, 5 studies (N = 1509 patients) of mixed methodological quality were included. At 6 months, 2LBA achieved better ulcer healing in comparison with 2LBB (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.10-2.24; P = .03) and 4LBA (OR, 1.93, 95% CI, 1.26-2.97; P = .05) in patients with newly diagnosed ulcers only. For a combined population with newly diagnosed and existing VLUs, healing outcomes were OR, 2.87; 95% CI, 1.06-7.77; P = .04, and OR, 16.51; 95% CI, 2.08-131.37; P = .008, for 2LBs and 4LBs, respectively. Results on slippage were inconclusive. Adverse events were infrequent and did not differ significantly between interventions. Lower 6-month NHS costs for the combined population (£2413 vs. £2707 or £2648) and for newly diagnosed patients (£3045 vs. £3842 or £4480) were observed comparing 2LBA with 2LBB or 4LBA. Also, 2LBA was associated with better health-related quality of life (HRQoL) at 6 months.Based on these findings, 2LBA may result in lower treatment costs and better ulcer healing and HRQoL compared with other multicomponent therapies, especially in patients with newly diagnosed VLUs. However, further high-quality research is needed, especially for outcomes such as slippage and bandage wear time.

Background/AimsUveitis is inflammation inside the eye. Our objective was to assess the cost-effectiveness of adalimumab compared with current practice (immunosuppressants and systemic corticosteroids) in patients with non-infectious intermediate, posterior or panuveitis and to identify areas for future research.MethodsA Markov model was built to estimate costs and benefits of the interventions. Systematic reviews were performed to identify the available relevant clinical and cost-effectiveness evidence. Data collected in two key randomised controlled trials (VISUAL I and VISUAL II) were used to estimate the interventions’ effectiveness compared with the trials’ comparator arms (placebo plus limited current practice (LCP)). The analysis was performed from the National Health Service and Personal Social Services perspective. Costs were calculated based on standard UK sources.ResultsThe estimated incremental cost-effectiveness ratios (ICERs) of adalimumab versus LCP for the base case are £92 600 and £318 075 per quality-adjusted life year (QALY) gained for active and inactive uveitis, respectively. In sensitivity analyses, the ICER varied from £15 579 to £120 653 and £35 642 to £800 775 per QALY for active and inactive uveitis.ConclusionThe estimated ICERs of adalimumab versus LCP are above generally accepted thresholds for cost-effectiveness in the UK. Adalimumab may be more cost-effective in patients with active uveitis at greater risk of blindness. However, there is an unmet need for additional primary data to provide more reliable estimates in several important areas, including effectiveness of adalimumab versus current practice (instead of LCP), incidence of long-term blindness, adalimumab effectiveness in avoiding blindness, and rates and time to remission while on adalimumab.

Background: A variety of instruments have been used to assess outcomes for patients with venous leg ulcers. This study sought to identify, evaluate and recommend the most appropriate patient reported outcomes (PROMs) for English-speaking patients with venous leg ulcers (VLUs). Method: This systematic review used a two-staged approach. Electronic searches of major databases including MEDLINE were completed in October 2015 and then updated in July 2016. Additional studies were identified from citation checking. Study selection, data extraction and quality assessment were undertaken independently by at least two reviewers. Evaluation and summary of measurement properties of identified PROMs were undertaken using standard and adapted study-relevant criteria. Results: Ten studies with data for three generic PROMS and six condition-specific measures were identified. No generic PROM showed adequate content and criterion validity; however the EQ-5D, Nottingham Health Profile (NHP) and 12-item Health Survey Short-Form had good acceptability with scores ranging from 80% to 91%. In general, the EQ-5D showed poor responsiveness in patients with VLUs. Condition-specific PROMs demonstrated poor criterion and construct validity. Overall, good internal consistency was demonstrated for the Venous Leg Ulcer Quality of Life (VLU-QOL) and the Sheffield Preference-based Venous Ulcer questionnaire (SPVU-5D). Test re-test reliability was also satisfactory for SPVU-5D and VeLUSET measures. Conclusions: The NHP and VLU-QOL seemed the most suitable PROMs for use by clinicians. A valid condition-specific PROM is still required.

Peripheral vascular disease is a major cause of death and disability. The extent to which volume influences outcome of lower limb (LL) vascular surgery remains unclear. This review evaluated the relationship between hospital/surgeon volume and outcome in LL surgery.Electronic databases-MEDLINE, Embase, the Cochrane Library Databases, Science Citation Index, and CINAHL-proceedings from conferences, citations, and references of included studies were searched. Studies from Europe, of adults undergoing LL vascular surgery reporting outcomes by hospital or surgeon volume were included. The quality of studies was assessed using a modified Cochrane Risk Of Bias Assessment Tool: for Non-Randomized Studies of Interventions (Robins1) tool. The association between hospital/surgeon volume and outcome was summarized using tables.Nine studies from different European countries, comprising 67,445 patients who had undergone diverse LL surgeries were included. The increase in hospital/surgeon volume was associated with a decrease in post-operative amputations (hospital at 30 days [odds ratio {OR}: 0.20, 95% confidence interval {CI} 0.29-0.45, P = 0.01; OR: 0.67, 95% CI 0.44-0.9, P = 0.05; OR: 0.96, 95% CI 0.92-1.00, P = 0.06], at 1 year [OR: 0.96, 95% CI 0.93-0.98, P = 0.002; OR: 0.66, 95% CI 0.52-0.84, P0.001; OR: 2.05, 95% CI 1.24-3.42, P = 0.01], surgeon at 30 days [OR: 0.53, 95% CI 0.36-0.87, P = 0.01; OR: 0.40, 95% CI 0.18-0.91, P = 0.03; OR: 0.41, 95% CI 0.24-0.69, P = 0.0006]). The evidence on an association between hospital/surgeon volume and mortality was contradictory, but mortality and amputations may covary by hospital volume. There were an insufficient number of studies reporting on the other variables to draw firm conclusions, but their results suggest that high-volume hospitals may undertake more repeated surgeries/revascularizations and limb salvage. The impact of hospital/surgical volume on adverse events and length of hospitalization could not be determined.High-volume hospitals/surgeons may undertake fewer amputations and mortality and amputations may covary. The finding that hospital and surgeon volume affected the number of secondary amputations has implications on reorganization of vascular surgery services. However, due to the small number and poor quality of some of the included studies, decisions on reorganization of LL vascular surgery services should be supplemented by results from clinical audits. There is need for standardization of definition of volume stratification of outcomes by patient's clinical conditions.

BackgroundNon-infectious intermediate uveitis, posterior uveitis and panuveitis are a heterogeneous group of inflammatory eye disorders. Management includes local and systemic corticosteroids, immunosuppressants and biological drugs.ObjectivesTo evaluate the clinical effectiveness and cost-effectiveness of subcutaneous adalimumab (Humira®; AbbVie Ltd, Maidenhead, UK) and a dexamethasone intravitreal implant (Ozurdex®; Allergan Ltd, Marlow, UK) in adults with non-infectious intermediate uveitis, posterior uveitis or panuveitis.Data sourcesElectronic databases and clinical trials registries including MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and the World Health Organization’s International Clinical Trials Registry Platform were searched to June 2016, with an update search carried out in October 2016.Review methodsReview methods followed published guidelines. A Markov model was developed to assess the cost-effectiveness of dexamethasone and adalimumab, each compared with current practice, from a NHS and Personal Social Services (PSS) perspective over a lifetime horizon, parameterised with published evidence. Costs and benefits were discounted at 3.5%. Substantial sensitivity analyses were undertaken.ResultsOf the 134 full-text articles screened, three studies (four articles) were included in the clinical effectiveness review. Two randomised controlled trials (RCTs) [VISUAL I (active uveitis) and VISUAL II (inactive uveitis)] compared adalimumab with placebo, with limited standard care also provided in both arms. Time to treatment failure (reduced visual acuity, intraocular inflammation, new vascular lesions) was longer in the adalimumab group than in the placebo group, with a hazard ratio of 0.50 [95% confidence interval (CI) 0.36 to 0.70;p p = 0.004) in the VISUAL II trial. The adalimumab group showed a significantly greater improvement than the placebo group in the 25-item Visual Function Questionnaire (VFQ-25) composite score in the VISUAL I trial (mean difference 4.20;p = 0.010) but not the VISUAL II trial (mean difference 2.12;p = 0.16). Some systemic adverse effects occurred more frequently with adalimumab than with placebo. One RCT [HURON (active uveitis)] compared a single 0.7-mg dexamethasone implant against a sham procedure, with limited standard care also provided in both arms. Dexamethasone provided significant benefits over the sham procedure at 8 and 26 weeks in the percentage of patients with a vitreous haze score of zero (p p ≤ 0.002) and the percentage of patients with a ≥ 5-point improvement in VFQ-25 score (p LimitationsThe clinical trials did not fully reflect clinical practice. Thirteen additional studies of clinically relevant comparator treatments were identified; however, network meta-analysis was not feasible. The model results are highly uncertain because of the limited evidence base.ConclusionsTwo RCTs of systemic adalimumab and one RCT of a unilateral, single dexamethasone implant showed significant benefits over placebo or a sham procedure. The ICERs for adalimumab were estimated to be above generally accepted thresholds for cost-effectiveness. The cost-effectiveness of dexamethasone was estimated to fall below standard thresholds. However, there is substantial uncertainty around the model assumptions. In future work, primary research should compare dexamethasone and adalimumab with current treatments over the long term and in important subgroups and consider how short-term improvements relate to long-term effects on vision.Study registrationThis study is registered as PROSPERO CRD42016041799.FundingThe National Institute for Health Research Health Technology Assessment programme.

Background Varicose veins can affect quality of life. Patient-reported outcome measures (PROMs) provide a direct report from the patient about the impact of the disease without interpretation from clinicians or anyone else. The aim of this study was to examine the quality of the psychometric evidence for PROMs used in patients with varicose veins. Methods A systematic review was undertaken to identify studies that reported the psychometric properties of generic and disease-specific PROMs in patients with varicose veins. Literature searches were conducted in databases including MEDLINE, up to July 2016. The psychometric criteria used to assess these studies were adapted from published recommendations in accordance with US Food and Drug Administration guidance. Results Nine studies were included which reported on aspects of the development and/or validation of one generic (36-Item Short Form Health Survey, SF-36®) and three disease-specific (Aberdeen Varicose Vein Questionnaire, AVVQ; Varicose Veins Symptoms Questionnaire, VVSymQ®; Specific Quality-of-life and Outcome Response – Venous, SQOR-V) PROMs. The evidence from included studies provided data to support the construct validity, test–retest reliability and responsiveness of the AVVQ. However, its content validity, including weighting of the AVVQ questions, was biased and based on the opinion of clinicians, and the instrument had poor acceptability. VVSymQ® displayed good responsiveness and acceptability rates. SF-36® was considered to have satisfactory responsiveness and internal consistency. Conclusion There is a scarcity of psychometric evidence for PROMs used in patients with varicose veins. These data suggest that AVVQ and SF-36® are the most rigorously evaluated PROMs in patients with varicose veins.

Background Hospitals that conduct more procedures on the carotid arteries may achieve better outcomes. In the context of ongoing reconfiguration of UK vascular services, this systematic review was conducted to evaluate the relationship between the volume of carotid procedures and outcomes, including mortality and stroke. Methods Searches of electronic databases identified studies that reported the effect of hospital or clinician volume on outcomes. Reference and citation searches were also performed. Inclusion was restricted to European populations on the basis that the model of healthcare delivery is similar across Europe, but differs from that in the USA and elsewhere. Analyses of hospital and clinician volume, and carotid endarterectomy (CEA) and carotid artery stenting (CAS) were conducted separately. Results Eleven eligible studies were identified (233 411 participants), five from the UK, two from Sweden, one each from Germany, Finland and Italy, and a combined German, Austrian and Swiss population. All studies were observational. Two large studies (179 736 patients) suggested an inverse relationship between hospital volume and mortality (number needed to treat (NNT) as low as 165), and combined mortality and stroke (NNT as low as 93), following CEA. The evidence was less clear for CAS; multiple analyses in three studies did not identify convincing evidence of an association. Limited data are available on the relationship between clinician volume and outcome in CAS; in CEA, an inverse relationship was identified by two of three small studies. Conclusion The evidence from the largest and highest-quality studies included in this review support the centralization of CEA.

BackgroundRheumatoid arthritis (RA) is a chronic, debilitating disease associated with reduced quality of life and substantial costs. It is unclear which tests and assessment tools allow the best assessment of prognosis in people with early RA and whether or not variables predict the response of patients to different drug treatments.ObjectiveTo systematically review evidence on the use of selected tests and assessment tools in patients with early RA (1) in the evaluation of a prognosis (review 1) and (2) as predictive markers of treatment response (review 2).Data sourcesElectronic databases (e.g. MEDLINE, EMBASE, The Cochrane Library, Web of Science Conference Proceedings; searched to September 2016), registers, key websites, hand-searching of reference lists of included studies and key systematic reviews and contact with experts.Study selectionReview 1 – primary studies on the development, external validation and impact of clinical prediction models for selected outcomes in adult early RA patients. Review 2 – primary studies on the interaction between selected baseline covariates and treatment (conventional and biological disease-modifying antirheumatic drugs) on salient outcomes in adult early RA patients.ResultsReview 1 – 22 model development studies and one combined model development/external validation study reporting 39 clinical prediction models were included. Five external validation studies evaluating eight clinical prediction models for radiographic joint damage were also included.c-statistics from internal validation ranged from 0.63 to 0.87 for radiographic progression (different definitions, six studies) and 0.78 to 0.82 for the Health Assessment Questionnaire (HAQ). Predictive performance in external validations varied considerably. Three models [(1) Active controlled Study of Patients receiving Infliximab for the treatment of Rheumatoid arthritis of Early onset (ASPIRE) C-reactive protein (ASPIRE CRP), (2) ASPIRE erythrocyte sedimentation rate (ASPIRE ESR) and (3) Behandelings Strategie (BeSt)] were externally validated using the same outcome definition in more than one population. Results of the random-effects meta-analysis suggested substantial uncertainty in the expected predictive performance of models in a new sample of patients. Review 2 – 12 studies were identified. Covariates examined included anti-citrullinated protein/peptide anti-body (ACPA) status, smoking status, erosions, rheumatoid factor status, C-reactive protein level, erythrocyte sedimentation rate, swollen joint count (SJC), body mass index and vascularity of synovium on power Doppler ultrasound (PDUS). Outcomes examined included erosions/radiographic progression, disease activity, physical function and Disease Activity Score-28 remission. There was statistical evidence to suggest that ACPA status, SJC and PDUS status at baseline may be treatment effect modifiers, but not necessarily that they are prognostic of response for all treatments. Most of the results were subject to considerable uncertainty and were not statistically significant.LimitationsThe meta-analysis in review 1 was limited by the availability of only a small number of external validation studies. Studies rarely investigated the interaction between predictors and treatment.Suggested research prioritiesCollaborative research (including the use of individual participant data) is needed to further develop and externally validate the clinical prediction models. The clinical prediction models should be validated with respect to individual treatments. Future assessments of treatment by covariate interactions should follow good statistical practice.ConclusionsReview 1 – uncertainty remains over the optimal prediction model(s) for use in clinical practice. Review 2 – in general, there was insufficient evidence that the effect of treatment depended on baseline characteristics.Study registrationThis study is registered as PROSPERO CRD42016042402.FundingThe National Institute for Health Research Health Technology Assessment programme.

Purpose: To estimate the economic impact of a TegadermTM chlorhexidine gluconate (CHG) gel dressing compared with a standard intravenous (i.v.) dressing (defined as non-antimicrobial transparent film dressing), used for insertion site care of short-term central venous and arterial catheters (intravascular catheters) in adult critical care patients using a cost-consequence model populated with data from published sources. Material and Methods: A decision analytical cost-consequence model was developed which assigned each patient with an indwelling intravascular catheter and a standard dressing, a baseline risk of associated dermatitis, local infection at the catheter insertion site and catheter-related bloodstream infections (CRBSI), estimated from published secondary sources. The risks of these events for patients with a Tegaderm CHG were estimated by applying the effectiveness parameters from the clinical review to the baseline risks. Costs were accrued through costs of intervention (i.e. Tegaderm CHG or standard intravenous dressing) and hospital treatment costs depended on whether the patients had local dermatitis, local infection or CRBSI. Total costs were estimated as mean values of 10,000 probabilistic sensitivity analysis (PSA) runs. Results: Tegaderm CHG resulted in an average cost-saving of £77 per patient in an intensive care unit. Tegaderm CHG also has a 98.5% probability of being cost-saving compared to standard i.v. dressings. Conclusions: The analyses suggest that Tegaderm CHG is a cost-saving strategy to reduce CRBSI and the results were robust to sensitivity analyses.

Parkinson's disease (PD) is a neurodegenerative disorder that is common in older individuals. PD patients have an increased risk of fractures compared to the general population, perhaps due to multiple falls. However, the fracture risk has not been fully assessed. To assess the impact of PD on the risk of hip and non-vertebral fractures, we conducted a systematic review and meta-analysis.\ud \ud \ud \ud Comprehensive searches of three key bibliographic databases were conducted to identify reviews and primary studies relating to the risk of fractures in patients with PD. Search terms included all relevant terms for Parkinson's disease and for fractures. We selected observational studies with data on the risk of fractures in adults with PD compared to controls without the diagnosis. Study quality was assessed using the Newcastle Ottawa Scale. The random-effects model was used to pool the results.\ud \ud \ud \ud Eighteen studies were included in the review. Seventeen independent studies (14 cohort and 3 case-control studies) were included in the hip fracture analysis. Nine studies (all cohorts, no case-control studies) were included in the non-vertebral fracture analysis. Study quality was judged to be moderate to good. Overall, PD patients had an increased risk for both hip fractures (2.40, 95% CI 2.04 to 2.82) and non-vertebral fractures (1.80, 95% CI 1.60 to 2.01) compared to controls. The relative risk for hip fractures was higher in men (2.93, 95% CI 2.05 to 4.18) than in women (1.81, 95% CI 1.61 to 2.04). There were no effects of the study design, geographical region, or criteria for diagnosing Parkinson's disease on these estimates of fracture risk.\ud \ud \ud \ud There is an increase in the risk of hip and non-vertebral fractures in patients with Parkinson's disease and we recommend a re-evaluation of the clinical guidelines on bone health in patients with PD to address this.

Objective: \ud Patient-reported outcome measures (PROMs) provide a way to measure the impact of a disease and its associated treatments on the quality of life from the patients’ perspective. The aim of this review was to identify PROMs that have been developed and/or validated in patients with carotid artery stenosis (CAS) undergoing revascularisation and to assess their psychometric properties and examine suitability for research and clinical use.\ud Methods: \ud Eight electronic databases including MEDLINE and CINAHL were searched using a two-stage search approach to identify studies reporting the development and/or validation of relevant PROMs in patients with CAS undergoing revascularisation. Supplementary citation searching and hand-searching reference lists of included studies were also undertaken. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) and Oxford criteria were used to assess the methodological quality of the included studies and the psychometric properties of the PROMs were evaluated using established assessment criteria.\ud Results: \ud Five studies reporting on six PROMs were included: 36-Item Short Form Health Survey (SF-36), Euro-QoL-5-Dimension Scale (EQ-5D), Hospital Anxiety and Depression Scale (HADS), Dizziness Handicap Inventory (DHI), Quality of life for carotid artery disease scale and a disease-specific PROM for CAS. The rigour of the psychometric assessment of the PROMs was variable with most only attempting to assess a single psychometric criterion. No study reported evidence on construct validity and test-retest reliability. Evidence for acceptability for the use of SF-36, EQ-5D and the disease-specific PROM were rated good in most studies. Only one study reported a Cronbach alpha score >0.70 as evidence of internal consistency. Overall, the psychometric evaluation of all included PROMs was rated as poor within the CAS population undergoing revascularisation.\ud Conclusions: \ud This review highlighted a lack of evidence in validated PROMs used for patients undergoing carotid artery revascularisation. As a result, the development and validation of a new PROM for this patient population is warranted in order to provide data which can supplement traditional clinical outcomes (stroke

Objective: To evaluate the relationship between the volume of abdominal aortic aneurysm (AAA) procedures undertaken and the primary outcome of mortality in Europe. Previous systematic reviews of this relationship are outdated and are overwhelmingly based on US data.\ud \ud Data sources: Comprehensive searching within MEDLINE and other bibliographic databases supplemented by citation searching and hand-searching of journals was undertaken to identify studies that reported the effect of hospital or clinician volume on any reported outcomes in adult, European populations, undergoing AAA repair and published in the last 10 years.\ud \ud Methods: Two reviewers conducted study selection with independent, duplicate data extraction and quality assessment. A planned meta-analysis was not conducted because of the high risk of bias, the likelihood of individual study subjects being included in more than one study and diversity in the clinical populations studied and methods used.\ud \ud Results: Sixteen studies (n = 237,074 participants) from the UK (n = 11 studies), Germany (n = 3 studies), Norway (n = 1 study), and one from the UK and Sweden were included. Data in the included studies came from administrative databases and clinical registries incorporating a variety of clinical and procedural groups; the study quality was limited by the use of observational study designs. Overall, the evidence favoured the existence of an inverse volume outcome relationship between hospital volume and mortality. Insufficient evidence was available to reach conclusions on the relationship between clinician volume and outcome and between hospital or clinician volume and secondary outcomes including complications and length of hospital stay.\ud \ud Conclusions: The evidence from this review suggests a relationship between the hospital volume of AAA procedures conducted and short-term mortality; however, as volume typically represents a complex amalgamation of factors further research will be useful to identify the core characteristics of volume that influence improved outcomes.

Background Peripheral arterial disease (PAD) is generally associated with considerable morbidity and reduced quality of life. Patient-reported outcome measures (PROMs) provide important information about the burden of disease and impact of treatment in affected patients. Objectives The objective of the review was to identify and appraise studies reporting the psychometric evaluation of PROMs administered to a specified population of patients with PAD with a view to recommending suitable PROMs. Methods A systematic review of peer-reviewed English language articles was undertaken to identify primary studies reporting psychometric properties of PROMs in English-speaking patients with various stages of PAD. Comprehensive searches were completed up until January 2015. Study selection, data extraction and quality assessment were undertaken independently by at least two researchers. Findings were presented as tabular and narrative summaries based on accepted guidance. Results Psychometric evaluation of 6 generic and 7 condition-specific PROMs reported in 14 studies contributed data to the review. The frequently reported measure was the SF-36 (n = 11 studies); others included the Walking Impairment Questionnaire (n = 8 studies), EQ-5D (n = 5 studies) and the Vascular Quality of Life Questionnaire (n = 3 studies). Studies included a diverse PAD population and varied in methodology, including approach to validation of PROMs. Conclusions Various PROMs have been validated in patients with PAD but no study provided evidence of a full psychometric evaluation in the patient population. Careful selection is required to identify reliable and valid PROMs to use in clinical and research settings. Electronic supplementary material The online version of this article (doi:10.1186/s12955-016-0563-y) contains supplementary material, which is available to authorized users.

INTRODUCTION:Uveitis is inflammation inside the eye whose underlying cause may be infectious or non-infectious. The objective of our study was to assess the cost-effectiveness of the dexamethasone implant and adalimumab compared with current practice (immunosuppressants and systemic corticosteroids) in patients with non-infectious intermediate, posterior or pan-uveitis.METHODS:A Markov model was built to estimate costs and benefits of the interventions. Systematic reviews were performed to identify the relevant evidence. Quality of life data collected in three key randomized-controlled trials (1-3) was used to estimate the interventions effectiveness compared with the trials comparator arms, which consisted of placebo plus limited current practice (LCP). An indirect treatment comparison between adalimumab and dexamethasone was considered inappropriate due to lack of necessary evidence. For adalimumab, patients with active and inactive uveitis were considered separately. Due to the short duration of the trials, the rate of blindness, an important complication of uveitis, was highly uncertain. Substantial exploratory analyses were therefore undertaken. The analysis was performed from the perspective of the National Health Service (NHS) and Personal Social Services (PSS). Costs were calculated based on standard United Kingdom sources.RESULTS:The estimated incremental cost-effectiveness (ICER) of dexamethasone compared with LCP was GBP19,509 per quality-adjusted life year (QALY) gained. The estimated ICER of adalimumab compared with LCP was GBP94,523 and GBP317,547 per QALY in patients with active and inactive uveitis respectively. The factors with the largest impact upon the ICERs were the rate of blindness and the proportion of cases of blindness avoided by interventions.CONCLUSIONS:Dexamethasone and adalimumab resulted in health gains, but at significant extra costs, especially adalimumab which is unlikely to be considered a cost-effective use of NHS resources. The results of the analysis are highly uncertain due to the limited availability of evidence on: the comparative effectiveness of dexamethasone, adalimumab and current practice; the effectiveness of treatments in avoiding blindness; and, the effectiveness of interventions in different subgroups.

INTRODUCTION:Patient-reported outcome measures (PROMs) provide a way to measure the impact of a disease and its associated treatments on the quality of life from the patients’ perspective. The aim of this review was to identify PROMs that have been developed and/or validated in patients with carotid artery disease (CAD) undergoing revascularization, and to assess their psychometric properties and examine suitability for research and clinical use.METHODS:Eight electronic databases including MEDLINE and CINAHL were searched from inception to May 2015 and updated in the MEDLINE database to February 2017. A two-stage search approach was used to identify studies reporting the development and/or validation of relevant PROMs in patients with CAD undergoing revascularization. Supplementary citation searching and hand-searching reference lists of included studies were also undertaken. The Consensus-based standards for the selection of health measurement instruments (COSMIN) and Oxford criteria were used to assess the methodological quality of the included studies, and the psychometric properties of the PROMs were evaluated using established assessment criteria.RESULTS:Six PROMs, reported in five studies, were identified: 36-Item Short Form Health Survey (SF-36), Euro-QoL-5-Dimension Scale (EQ-5D), Hospital Anxiety and Depression Scale (HADS), Dizziness Handicap Inventory (DHI), Quality of life for CAD scale by Ivanova 2015 and a disease-specific PROM designed by Stolker 2010. The rigour of the psychometric assessment of the PROMs were variable with most only attempting to assess a single psychometric criterion. No study reported evidence on criterion validity and test-retest reliability. The overall psychometric evaluation of all included PROMs was rated as poor.CONCLUSIONS:This review highlighted a lack of evidence in validated PROMs used for patients undergoing carotid artery revascularization. As a result, the development and validation of a new PROM for this patient population is warranted in order to provide data which can supplement traditional clinical outcomes (stroke >30 days post-procedural, myocardial infarction and death), and capture changes in health status and quality of life in patients to help inform treatment decisions.

BackgroundNon-invasive ventilation (NIV), in the form of continuous positive airway pressure (CPAP) or bilevel inspiratory positive airway pressure (BiPAP), is used in hospital to treat patients with acute respiratory failure. Pre-hospital NIV may be more effective than in-hospital NIV but requires additional ambulance service resources.ObjectivesWe aimed to determine the clinical effectiveness and cost-effectiveness of pre-hospital NIV compared with usual care for adults presenting to the emergency services with acute respiratory failure and to identify priorities for future research.Data sourcesFourteen electronic databases and research registers (including MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, and Cumulative Index to Nursing and Allied Health Literature) were searched from inception to August 2013, supplemented by hand-searching reference lists and contacting experts in the field.Review methodsWe included all randomised or quasi-randomised controlled trials of pre-hospital NIV in patients with acute respiratory failure. Methodological quality was assessed according to established criteria. An aggregate data network meta-analysis (NMA) of mortality and intubation was used to jointly estimate intervention effects relative to usual care. A NMA, using individual patient-level data (IPD) and aggregate data where IPD were not available, was carried out to assess whether or not covariates were treatment effect modifiers. A de novo economic model was developed to explore the costs and health outcomes when pre-hospital NIV (specifically CPAP provided by paramedics) and standard care (in-hospital NIV) were applied to a hypothetical cohort of patients with acute respiratory failure.ResultsThe literature searches identified 2284 citations. Of the 10 studies that met the inclusion criteria, eight were randomised controlled trials and two were quasi-randomised trials (six CPAP; four BiPAP; sample sizes 23–207 participants). IPD were available from seven trials (650 patients). The aggregate data NMA suggested that CPAP was the most effective treatment in terms of mortality (probability = 0.989) and intubation rate (probability = 0.639), and reduced both mortality [odds ratio (OR) 0.41, 95% credible interval (CrI) 0.20 to 0.77] and intubation rate (OR 0.32, 95% CrI 0.17 to 0.62) compared with standard care. The effect of BiPAP on mortality (OR 1.94, 95% CrI 0.65 to 6.14) and intubation rate (OR 0.40, 95% CrI 0.14 to 1.16) compared with standard care was uncertain. The combined IPD and aggregate data NMA suggested that sex was a statistically significant treatment effect modifier for mortality. The economic analysis showed that pre-hospital CPAP was more effective and more expensive than standard care, with an incremental cost-effectiveness ratio of £20,514 per quality-adjusted life-year (QALY) and a 49.5% probability of being cost-effective at the £20,000-per-QALY threshold. Variation in the incidence of eligible patients had a marked impact on cost-effectiveness and the expected value of sample information for a future randomised trial.LimitationsThe meta-analysis lacked power to detect potentially important differences in outcome (particularly for BiPAP), the intervention was not always compared with the best alternative care (in-hospital NIV) in the primary studies and findings may not be generalisable.ConclusionsPre-hospital CPAP can reduce mortality and intubation rates, but cost-effectiveness is uncertain and the value of further randomised evaluation depends on the incidence of suitable patients. A feasibility study is required to determine if a large pragmatic trial of clinical effectiveness and cost-effectiveness is appropriate.Study registrationThe study is registered as PROSPERO CRD42012002933.FundingThe National Institute for Health Research Health Technology Assessment programme.

OBJECTIVES: This meta-analysis aimed to determine the effectiveness of prehospital continuous positive airway pressure (CPAP) or bilevel inspiratory positive airway pressure (BiPAP) in acute respiratory failure. METHODS: Fourteen electronic databases and research registers were searched from inception to August 2013. Randomized or quasi-randomized controlled trials that reported mortality or intubation rate for prehospital CPAP or BiPAP were selected and compared to a relevant comparator in patients with acute respiratory failure. An aggregate data network meta-analysis was used to jointly estimate intervention effects relative to standard care. A network meta-analysis using a mixture of individual patient-level data and aggregate data was carried out to assess potential treatment effect modifiers. RESULTS: Eight randomized and two quasi-randomized controlled trials (six CPAP, four BiPAP, sample sizes 23 to 207) were identified. The aggregate data network meta-analysis suggested that CPAP was the most effective treatment in terms of mortality (probability = 0.989) and intubation rate (probability = 0.639) and reduced both mortality (odds ratio [OR] = 0.41; 95% credible interval [CrI] = 0.20 to 0.77) and intubation rate (OR = 0.32; 95% CrI = 0.17 to 0.62), compared to standard care. The effect of BiPAP on mortality (OR = 1.94; 95% CrI = 0.65 to 6.14) and intubation rate (OR = 0.40; 95% CrI = 0.14 to 1.16) was uncertain. The network meta-analysis using individual patient-level data and aggregate data suggested that sex was a modifier of the effect of treatment on mortality. CONCLUSIONS: Prehospital CPAP can reduce mortality and intubation rates compared to standard care, while the effectiveness of prehospital BiPAP is uncertain. peerReviewed

Objective To investigate the clinical effectiveness and cost-effectiveness of transthoracic echocardiography (TTE) in all patients who are newly diagnosed with atrial fibrillation (AF). Design Narrative synthesis reviews were conducted on the prognostic and diagnostic accuracy of TTE for, and prevalence of, pathologies in patients with AF. Databases were searched from inception. MEDLINE searches were conducted from March to August 2010, and reference lists of articles checked. There were 44 diagnostic accuracy studies, five prognostic studies, and 16 prevalence studies accepted into the review. Given the complexity of the many pathologies identified by TTE, the variety of potential changes to clinical management, and paucity of data, the model focused on changes to oral anticoagulation (OAC). The mathematical model assessed the cost-effectiveness of TTE for patients with AF who were not routinely given OAC, assuming, if left atrial abnormality was detected, that the higher risk of stroke warranted OAC; this meant that patients with a CHADS2 (cardiac failure, hypertension, age, diabetes, stroke doubled) score of 0 [dabigatran etexilate (Pradaxa, Boehringer Ingelheim)/rivaroxaban (Xarelto, Bayer Schering)] or 0/1 (warfarin) were included. A simplified approach evaluated the additional quality-adjusted life-years (QALYs) required in order for TTE to be perceived as cost-effective at a threshold of £20,000 per QALY. Setting Transthoracic echocardiography is usually performed in cardiology clinics but may be used in primary or non-specialist secondary care. Participants Patients with newly diagnosed AF. Intervention Transthoracic echocardiography. Main outcome measures Prognosis, diagnostic sensitivity or specificity of TTE, prevalence of pathologies in patients with AF, cost-effectiveness and QALYs. Results Prognostic studies indicated that TTE-diagnosed left ventricular dysfunction, increased left atrial diameter and valvular abnormality were significantly associated with an increased risk of stroke, mortality or thromboembolism. There was a high prevalence (around 25-30%) of ischaemic heart disease, valvular heart disease and heart failure in patients with AF. Diagnostic accuracy of TTE was high, with most pathologies having specificity of ≥ 0.8 and sensitivity of ≥ 0.6. The mathematical model predicted that when the CHADS2 tool is used the addition of TTE in identifying patients with left atrial abnormality appears to be cost-effective for informing some OAC decisions. In the simplified approach a threshold of 0.0033 was required for a TTE to be cost-effective. Conclusions When CHADS2 was used, the addition of TTE in identifying patients with left atrial abnormality was cost-effective for informing some OAC decisions. A simple analysis indicates that the number of QALYs required for TTE to be cost-effective is small, and that if benefits beyond those associated with a reduction in stroke are believed probable then TTE is likely to be cost-effective in all scenarios. Our findings suggest that further research would be useful, following up newly diagnosed patients with AF who have undergone TTE, to study treatments given as a result of TTE diagnoses and subsequent cardiovascular events. This could identify additional benefits of routine testing, beyond stroke prevention. Studies assessing the proportion of people with a CHADS2 score of 0 or 1 that have left atrial abnormality would provide better estimates of the cost-effectiveness of TTE, and allow more accurate estimates of the sensitivity and specificity of TTE for identifying left atrial abnormality in AF to be obtained. Study registration PROSPERO CRD42011001354. Funding The National Institute for Health Research Health Technology Assessment programme.

Background\ud \ud Health state utility values (HSUVs) are important in the assessment of the cost effectiveness of new interventions. In the case of visual conditions, models generally tend have tended to be built around a set of health states defined by visual acuity (VA). The aim of this review was to assess the impact of VA on HSUVs in patients with diabetic retinopathy, diabetic macular oedema or age-related macular degeneration.\ud \ud Methods\ud \ud A systematic literature search was undertaken in major bibliographic databases to identify articles reporting on the relationship between HSUVs and vision. Data were extracted for population characteristics, visual levels and estimated utilities. Evidence from reported statistical models, where available, was considered in the evaluation of vision in the better-seeing eye and the worse-seeing eye. Due to the heterogeneity of included studies, a narrative synthesis was undertaken.\ud \ud Results\ud \ud Of the 17 relevant studies, 9 studies had data that could be used in the analysis of the impact of vision on HSUVs. Visual loss was associated with a marked impact on health utilities. However, the relationship was not comparable between conditions or by measure of HSUVs. Key results included the finding that overall, self-rated time-trade off estimates were more likely to discriminate between different VA levels than EQ-5D values. Additionally, a stronger correlation was observed between HSUVs and better-seeing eye VA compared to worse-seeing eye VA.\ud \ud Conclusions\ud \ud Visual acuity has a significant impact on HSUVs. Nevertheless, care must be taken in the interpretation and use of estimates in cost-effectiveness models due to differences in measures and population diversity.\ud

Objectives To assess the safety of intravitreal bevacizumab (IVB) as a monotherapy and to evaluate the relationship between quality of treatment and adverse events. Data sources Cochrane Library, Ovid MEDLINE, MEDLINE in-process, Ovid EMBASE and Toxicology Literature Online (TOXLINE) from January 2009 to May 2012. Studies included in an earlier systematic review were also assessed for inclusion. Study eligibility criteria, participants and interventions Randomised controlled trials (RCTs), controlled trials or observational studies including ≥10 participants reporting adverse events data following IVB monotherapy as a primary treatment in patients (aged 18 years or more) with any eye condition were included. Study appraisal and synthesis methods Study selection was undertaken independently by a minimum of two reviewers using pre-defined criteria. Data abstraction and quality assessment were performed by one reviewer, and then checked by a second reviewer. Study quality was assessed for only RCTs in accordance to the Cochrane Risk of Bias Tool. Additional items relating to safety data were also assessed. Results were tabulated or meta-analysed as appropriate. Results 22 RCTs and 67 observational studies were included. Only two RCTs reported valid safety data. Rates of serious adverse events following treatment were low. There was insufficient data to explore the relationship between the incidence of adverse events and quality of IVB injection. Limitations A majority of relevant existing studies were characterised by small sample sizes, unclear diagnostic criteria and reporting of safety outcomes. Conclusions and implications of key findings Available evidence demonstrates low rates of serious local and systemic adverse events following treatment. However, the role of IVB quality in the incidence of adverse events remains unclear. Robust evidence is needed to examine the relationship between the incidence of adverse events and variables such as injection techniques, pre-existing risk factors (eg, immunosuppression, cross-contamination) and quality of IVB treatment.