BackgroundHigh fractions of exhaled nitric oxide (FeNO) in the breath of patients with symptoms of asthma are correlated with high levels of eosinophils and indicate that a patient is likely to respond to inhaled corticosteroids. This may have a role in the diagnosis and management of asthma.ObjectiveTo assess the diagnostic accuracy, clinical effectiveness and cost-effectiveness of the hand-held electrochemical devices NIOX MINO®(Aerocrine, Solna, Sweden), NIOX VERO®(Aerocrine) and NObreath®(Bedfont Scientific, Maidstone, UK) for the diagnosis and management of asthma.Data sourcesSystematic searches were carried out between March 2013 and April 2013 from database inception. Databases searched included MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, Science Citation Index Expanded and Conference Proceedings Citation Index – Science. Trial registers such as ClinicalTrials.gov and themetaRegister of Controlled Trials were also searched in March 2013. All searches were updated in September 2013.Review methodsA rapid review was conducted to assess the equivalence of hand-held and chemiluminescent FeNO monitors. Systematic reviews of diagnostic accuracy and management efficacy were conducted. A systematic review of economic analyses was also conducted and two de novo health economic models were developed. All three reviews were undertaken according to robust high-quality methodology.ResultsThe rapid review (27 studies) found varying levels of agreement between monitors (Bland–Altman 95% limits of agreement up to ±10 parts per billion), with better agreement at lower FeNO values. Correlation was good (generallyr > 0.9). The diagnostic accuracy review identified 22 studies in adults (all ages) and four in children. No studies used NObreath or NIOX VERO and seven used NIOX MINO. Estimates of diagnostic accuracy varied widely. FeNO used in combination with another test altered diagnostic accuracy only slightly. High levels of heterogeneity precluded meta-analysis. Limited observations included that FeNO may be more reliable and useful as a rule-in than as a rule-out test; lower cut-off values in children and in smokers may be appropriate; and FeNO may be less reliable in the elderly. The management review identified five randomised controlled trials in adults, one in pregnant asthmatics and seven in children. Despite clinical heterogeneity, exacerbation rates were lower in all studies but not generally statistically significantly so. Effects on inhaled corticosteroid (ICS) use were inconsistent, possibly because of differences in management protocols, differential effectiveness in adults and children and differences in population severity. One UK diagnostic model and one management model were identified. Aerocrine also submitted diagnostic and management models. All had significant limitations including short time horizons and the selective use of efficacy evidence. The de novo diagnostic model suggested that the expected difference in quality-adjusted life-year (QALY) gains between diagnostic options is likely to be very small. Airway hyper-responsiveness by methacholine challenge test is expected to produce the greatest QALY gain but with an expected incremental cost-effectiveness ratio (ICER) compared with FeNO (NObreath) in combination with bronchodilator reversibility of £1.125M per QALY gained. All remaining options are expected to be dominated. The de novo management model indicates that the ICER of guidelines plus FeNO monitoring using NObreath compared with guidelines alone in children is expected to be approximately £45,200 per QALY gained. Within the adult subgroup, FeNO monitoring using NObreath compared with guidelines alone is expected to have an ICER of approximately £2100 per QALY gained. The results are particularly sensitive to assumptions regarding changes in ICS use over time, the number of nurse visits for FeNO monitoring and duration of effect.ConclusionsLimitations of the evidence base impose considerable uncertainty on all analyses. Equivalence of devices was assumed but not assured. Evidence for diagnosis is difficult to interpret in the context of inserting FeNO monitoring into a diagnostic pathway. Evidence for management is also inconclusive, but largely consistent with FeNO monitoring resulting in fewer exacerbations, with a small or zero reduction in ICS use in adults and a possible increased ICS use in children or patients with more severe asthma. It is unclear which specific management protocol is likely to be most effective. The economic analysis indicates that FeNO monitoring could have value in diagnostic and management settings. The diagnostic model indicates that FeNO monitoring plus bronchodilator reversibility dominates many other diagnostic tests. FeNO-guided management has the potential to be cost-effective, although this is largely dependent on the duration of effect. The conclusions drawn from both models require strong technical value judgements with respect to several aspects of the decision problem in which little or no empirical evidence exists. There are many potential directions for further work, including investigations into which management protocol is best and long-term follow-up in both diagnosis and management studies.Study registrationThis study is registered as PROSPERO CRD42013004149.FundingThe National Institute for Health Research Health Technology Assessment programme.

As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer of vedolizumab (Takeda UK) to submit evidence of the clinical effectiveness and cost-effectiveness of vedolizumab for the treatment of patients with moderate-to-severe active ulcerative colitis (UC). The Evidence Review Group (ERG) produced a critical review of the evidence for the clinical effectiveness and cost-effectiveness of the technology, based upon the company's submission to NICE. The evidence was derived mainly from the GEMINI1 trial, which is a Phase III, multicentre, randomised, doubleblind, placebo-controlled trial designed to evaluate the efficacy and safety of vedolizumab as an induction and maintenance treatment in patients with moderate-to-severe active UC who had an inadequate response to, loss of response to, or intolerance to conventional therapy or anti-Tumour necrosis factor-alpha (TNF-). The clinical evidence showed that vedolizumab performed significantly better than placebo in both the induction and maintenance phases. In the post-hoc subgroup analyses, patients with or without prior anti-TNF-therapy, vedolizumab performed better then placebo (p-value not reported). In addition, a greater improvement in health-related quality of life was observed in patients treated with vedolizumab and the frequency and types of adverse events were similar between the vedolizumab and placebo group but the evidence was limited to shortterm follow-up. There were a number of limitations and uncertainties in the clinical evidence base which warrant caution in its interpretation. In particular, the post-hoc subgroup analyses and high dropout rates in the maintenance phase of the GEMINI1 trial. The company also presented a network meta-analysis of vedolizumab versus other biologics therapies indicated for moderate-to-severe UC. However, the ERG considered that the results presented may have underestimated the uncertainty in treatment effects since fixed effects models were Key Points for Decision Makers Vedolizumab appears to be more effective in both the induction and maintenance phase compared with placebo in patients with moderate-to-severe active ulcerative colitis who have had an inadequate response to, loss of response to, or intolerance to conventional therapy or TNF-inhibitor. However, the subgroup analyses for patients with or without prior TNF-inhibitor therapy were post-hoc and the study was not powered for these assessments.  The findings of the network meta-analysis of vedolizumab versus TNF-inhibitor are limited due to a number of uncertainties in treatment effects. In addition, there is currently no head-to-head randomised 3 controlled trial comparing vedolizumab to other biologic therapies indicated for moderate-to-severe ulcerative colitis.  The National Institute for Health and Care Excellence (NICE) Appraisal Committee recommended vedolizumab within its licence indication but only if the company provides vedolizumab with the discount agr...

The aim of this review was to evaluate the clinical effectiveness of fractional exhaled nitric oxide (FeNO) measured in a clinical setting for the management of asthma in adults.13 electronic databases were searched and studies were selected against predefined inclusion criteria. Quality assessment was conducted using QUADAS-2. Class effect meta-analyses were performed.Six studies were included. Despite high levels of heterogeneity in multiple study characteristics, exploratory class effect meta-analyses were conducted. Four studies reported a wider definition of exacerbation rates (major or severe exacerbation) with a pooled rate ratio of 0.80 (95% CI 0.63-1.02). Two studies reported rates of severe exacerbations (requiring oral corticosteroid use) with a pooled rate ratio of 0.89 (95% CI 0.43-1.72). Inhaled corticosteroid use was reported by four studies, with a pooled standardised mean difference of −0.24 (95% CI −0.56-0.07). No statistically significant differences for health-related quality of life or asthma control were found.FeNO guided management showed no statistically significant benefit in terms of severe exacerbations or inhaled corticosteroid use, but showed a statistically significant reduction in exacerbations of any severity. However, further research is warranted to clearly define which management protocols (including cut-off points) offer best efficacy and which patient groups would benefit the most. @ERSpublications FeNO testing for adult asthma management may confer clinical benefit, but research is needed to establish its role

ObjectivesTo assess the safety of intravitreal bevacizumab (IVB) as a monotherapy and to evaluate the relationship between quality of treatment and adverse events.Data sourcesCochrane 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 interventionsRandomised 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 methodsStudy 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.Results22 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.LimitationsA majority of relevant existing studies were characterised by small sample sizes, unclear diagnostic criteria and reporting of safety outcomes.Conclusions and implications of key findingsAvailable 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.

BackgroundA 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 outcome measures (PROMs) for English‐speaking patients with venous leg ulcers.MethodsThis systematic review used a two‐stage search 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 done using standard and adapted study‐relevant criteria.ResultsTen studies with data for four generic PROMS and six condition‐specific measures were identified. No generic PROM showed adequate content and criterion validity; however, the EuroQoL Five Dimensions (EQ‐5D™), Nottingham Health Profile (NHP) and 12‐item Short‐Form Health Survey (SF‐12®) had good acceptability. In general, the EQ‐5D™ showed poor responsiveness in patients with venous leg ulcers. Most condition‐specific PROMs demonstrated poor criterion and construct validity. Overall, there was some evidence of internal consistency for the Venous Leg Ulcer Quality of Life (VLU‐QoL) and the Sheffield Preference‐based Venous Ulcer questionnaire (SPVU‐5D). Test–retest reliability was satisfactory for the Venous Leg Ulcer Self‐Efficacy Tool (VeLUSET).ConclusionThe NHP and VLU‐QoL questionnaire seemed the most suitable PROMs for use by clinicians. However, a valid condition‐specific PROM is still required.