Nicola J. Cooper

Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial

BACKGROUND Severe acute respiratory failure in adults causes high mortality despite improvements in ventilation techniques and other treatments (eg, steroids, prone positioning, bronchoscopy, and inhaled nitric oxide). We aimed to delineate the safety, clinical efficacy, and cost-effectiveness of extracorporeal membrane oxygenation (ECMO) compared with conventional ventilation support. METHODS In this UK-based multicentre trial, we used an independent central randomisation service to randomly assign 180 adults in a 1:1 ratio to receive continued conventional management or referral to consideration for treatment by ECMO. Eligible patients were aged 18-65 years and had severe (Murray score >3.0 or pH <7.20) but potentially reversible respiratory failure. Exclusion criteria were: high pressure (>30 cm H(2)O of peak inspiratory pressure) or high FiO(2) (>0.8) ventilation for more than 7 days; intracranial bleeding; any other contraindication to limited heparinisation; or any contraindication to continuation of active treatment. The primary outcome was death or severe disability at 6 months after randomisation or before discharge from hospital. Primary analysis was by intention to treat. Only researchers who did the 6-month follow-up were masked to treatment assignment. Data about resource use and economic outcomes (quality-adjusted life-years) were collected. Studies of the key cost generating events were undertaken, and we did analyses of cost-utility at 6 months after randomisation and modelled lifetime cost-utility. This study is registered, number ISRCTN47279827. FINDINGS 766 patients were screened; 180 were enrolled and randomly allocated to consideration for treatment by ECMO (n=90 patients) or to receive conventional management (n=90). 68 (75%) patients actually received ECMO; 63% (57/90) of patients allocated to consideration for treatment by ECMO survived to 6 months without disability compared with 47% (41/87) of those allocated to conventional management (relative risk 0.69; 95% CI 0.05-0.97, p=0.03). Referral to consideration for treatment by ECMO led to a gain of 0.03 quality-adjusted life-years (QALYs) at 6-month follow-up [corrected]. A lifetime model predicted the cost per QALY of ECMO to be pound19 252 (95% CI 7622-59 200) at a discount rate of 3.5%. INTERPRETATION We recommend transferring of adult patients with severe but potentially reversible respiratory failure, whose Murray score exceeds 3.0 or who have a pH of less than 7.20 on optimum conventional management, to a centre with an ECMO-based management protocol to significantly improve survival without severe disability. This strategy is also likely to be cost effective in settings with similar services to those in the UK. FUNDING UK NHS Health Technology Assessment, English National Specialist Commissioning Advisory Group, Scottish Department of Health, and Welsh Department of Health.

Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis

Objective To quantify the effectiveness of pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance. Data sources Medline, Embase, and the Cochrane library searched up to July 2006. Expert opinions sought and reference lists of identified studies and any relevant published reviews checked. Study selection Randomised controlled trials that evaluated interventions to delay or prevent type 2 diabetes in individuals with impaired glucose tolerance. Results 21 trials met the inclusion criteria, of which 17, with 8084 participants with impaired glucose tolerance, reported results in enough detail for inclusion in the meta-analyses. From the meta-analyses the pooled hazard ratios were 0.51 (95% confidence interval 0.44 to 0.60) for lifestyle interventions v standard advice, 0.70 (0.62 to 0.79) for oral diabetes drugs v control, 0.44 (0.28 to 0.69) for orlistat v control, and 0.32 (0.03 to 3.07) for the herbal remedy jiangtang bushen recipe v standard diabetes advice. These correspond to numbers needed to treat for benefit (NNTB) and harm (NNTH) of 6.4 for lifestyle (95% credible interval, NNTB 5.0 to NNTB 8.4), 10.8 for oral diabetes drugs (NNTB 8.1 to NNTB 15.0), 5.4 for orlistat (NNTB 4.1 to NNTB 7.6), and 4.0 for jiangtang bushen (NNTH 16.9 to NNTB 24.8). Conclusions Lifestyle and pharmacological interventions reduce the rate of progression to type 2 diabetes in people with impaired glucose tolerance. Lifestyle interventions seem to be at least as effective as drug treatment.

Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials

Abstract Objective To review the clinical effectiveness of oseltamivir and zanamivir for the treatment and prevention of influenza A and B. Design Systematic review and meta-analyses of randomised controlled trials. Data sources Published studies were retrieved from electronic bibliographic databases; supplementary data were obtained from the manufacturers. Selection of studies Randomised controlled, double blind trials that were published in English, had data available before 31 December 2001, evaluated treatment or prevention of naturally occurring influenza with zanamivir or oseltamivir (if given using the formulation and dosage licensed for clinical use), and reported at least one end point of relevance. Review methods The main outcome measures were the median time to the alleviation of symptoms (for treatment trials) and number of flu episodes avoided (for prevention trials). Three population groups were defined: children aged 12 years and under; otherwise healthy individuals aged 12 to 65 years; and “high risk” individuals (those with certain chronic medical conditions or aged 65 years and older). Results Seventeen treatment trials and seven prevention trials identified met the inclusion criteria. All trials included compared one of the drugs against placebo or standard care. Treatment of children, otherwise healthy individuals, and high risk populations with zanamivir reduced the median duration of symptoms in days respectively by 1.0 (95% confidence interval 0.5 to 1.5), 0.8 (0.3 to 1.3), and 0.9 (−0.1 to 1.9) for the intention to treat population. The corresponding results, in days, for oseltamivir were 0.9 (0.3 to 1.5), 0.9 (0.3 to 1.4), and 0.4 (−0.7 to 1.4). The effect of giving zanamivir and oseltamivir prophylactically resulted in a relative reduction of 70-90% in the odds of developing flu, depending on the strategy adopted and the population studied. Conclusions Evidence from randomised controlled trials consistently supports the view that both oseltamivir and zanamivir are clinically effective for treating and preventing flu. However, evidence is limited for the treatment of certain populations and for all prevention strategies.

Bayesian methods for evidence synthesis in cost-effectiveness analysis

Recently, health systems internationally have begun to use cost-effectiveness research as formal inputs into decisions about which interventions and programmes should be funded from collective resources. This process has raised some important methodological questions for this area of research. This paper considers one set of issues related to the synthesis of effectiveness evidence for use in decision-analytic cost-effectiveness (CE) models, namely the need for the synthesis of all sources of available evidence, although these may not ‘fit neatly’ into a CE model.Commonly encountered problems include the absence of head-to-head trial evidence comparing all options under comparison, the presence of multiple endpoints from trials and different follow-up periods. Full evidence synthesis for CE analysis also needs to consider treatment effects between patient subpopulations and the use of nonrandomised evidence.Bayesian statistical methods represent a valuable set of analytical tools to utilise indirect evidence and can make a powerful contribution to the decision-analytic approach to CE analysis. This paper provides a worked example and a general overview of these methods with particular emphasis on their use in economic evaluation.

Meta-analysis of randomized clinical trials comparing open and laparoscopic inguinal hernia repair

The aim was to conduct a meta‐analysis of the randomized evidence to determine the relative merits of laparoscopic (LIHR) and open (OIHR) inguinal hernia repair.

Use of Indirect and Mixed Treatment Comparisons for Technology Assessment

Indirect and mixed treatment comparison (MTC) approaches to synthesis are logical extensions of more established meta-analysis methods. They have great potential for estimating the comparative effectiveness of multiple treatments using an evidence base of trials that individually do not compare all treatment options. Connected networks of evidence can be synthesized simultaneously to provide estimates of the comparative effectiveness of all included treatments and a ranking of their effectiveness with associated probability statements.The potential of the use of indirect and MTC methods in technology assessment is considerable, and would allow for a more consistent assessment than simpler alternative approaches. Although such models can be viewed as a logical and coherent extension of standard pair-wise meta-analysis, their increased complexity raises some unique issues with far-reaching implications concerning how we use data in technology assessment, while simultaneously raising searching questions about standard pair-wise meta-analysis. This article reviews pair-wise meta-analysis and indirect and MTC approaches to synthesis, clearly outlining the assumptions involved in each approach. It also raises the issues that the National Institute for Health and Clinical Excellence (NICE) needed to consider in updating their 2004 Guide to the Methods of Technology Appraisal, if such methods are to be used in their technology appraisals.

Different strategies for screening and prevention of type 2 diabetes in adults: cost effectiveness analysis

Objective To compare four potential screening strategies, and subsequent interventions, for the prevention and treatment of type 2 diabetes: (a) screening for type 2 diabetes to enable early detection and treatment, (b) screening for type 2 diabetes and impaired glucose tolerance, intervening with lifestyle interventions in those with a diagnosis of impaired glucose tolerance to delay or prevent diabetes, (c) as for (b) but with pharmacological interventions, and (d) no screening. Design Cost effectiveness analysis based on development and evaluation of probabilistic, comprehensive economic decision analytic model, from screening to death. Setting A hypothetical population, aged 45 at time of screening, with above average risk of diabetes. Data sources Published clinical trials and epidemiological studies retrieved from electronic bibliographic databases; supplementary data obtained from the Department of Health statistics for England and Wales, the screening those at risk (STAR) study, and the Leicester division of the ADDITION study. Methods A hybrid decision tree/Markov model was developed to simulate the long term effects of each screening strategy, in terms of both clinical and cost effectiveness outcomes. The base case model assumed a 50 year time horizon with discounting of both costs and benefits at 3.5%. Sensitivity analyses were carried out to investigate assumptions of the model and to identify which model inputs had most impact on the results. Results Estimated costs for each quality adjusted life year (QALY) gained (discounted at 3.5% a year for both costs and benefits) were £14 150 (€17 560;

Assessment of regression-based methods to adjust for publication bias through a comprehensive simulation study

27 860) for screening for type 2 diabetes, £6242 for screening for diabetes and impaired glucose tolerance followed by lifestyle interventions, and £7023 for screening for diabetes and impaired glucose tolerance followed by pharmacological interventions, all compared with no screening. At a willingness-to-pay threshold of £20 000 the probability of the intervention being cost effective was 49%, 93%, and 85% for each of the active screening strategies respectively. Conclusions Screening for type 2 diabetes and impaired glucose tolerance, with appropriate intervention for those with impaired glucose tolerance, in an above average risk population aged 45, seems to be cost effective. The cost effectiveness of a policy of screening for diabetes alone, which offered no intervention to those with impaired glucose tolerance, is still uncertain.

Addressing between-study heterogeneity and inconsistency in mixed treatment comparisons: Application to stroke prevention treatments in individuals with non-rheumatic atrial fibrillation

BackgroundIn meta-analysis, the presence of funnel plot asymmetry is attributed to publication or other small-study effects, which causes larger effects to be observed in the smaller studies. This issue potentially mean inappropriate conclusions are drawn from a meta-analysis. If meta-analysis is to be used to inform decision-making, a reliable way to adjust pooled estimates for potential funnel plot asymmetry is required.MethodsA comprehensive simulation study is presented to assess the performance of different adjustment methods including the novel application of several regression-based methods (which are commonly applied to detect publication bias rather than adjust for it) and the popular Trim & Fill algorithm. Meta-analyses with binary outcomes, analysed on the log odds ratio scale, were simulated by considering scenarios with and without i) publication bias and; ii) heterogeneity. Publication bias was induced through two underlying mechanisms assuming the probability of publication depends on i) the study effect size; or ii) the p-value.ResultsThe performance of all methods tended to worsen as unexplained heterogeneity increased and the number of studies in the meta-analysis decreased. Applying the methods conditional on an initial test for the presence of funnel plot asymmetry generally provided poorer performance than the unconditional use of the adjustment method. Several of the regression based methods consistently outperformed the Trim & Fill estimators.ConclusionRegression-based adjustments for publication bias and other small study effects are easy to conduct and outperformed more established methods over a wide range of simulation scenarios.

Novel methods to deal with publication biases: secondary analysis of antidepressant trials in the FDA trial registry database and related journal publications

Mixed treatment comparison models extend meta-analysis methods to enable comparisons to be made between all relevant comparators in the clinical area of interest. In such modelling it is imperative that potential sources of variability are explored to explain both heterogeneity (variation in treatment effects between trials within pairwise contrasts) and inconsistency (variation in treatment effects between pairwise contrasts) to ensure the validity of the analysis.The objective of this paper is to extend the mixed treatment comparison framework to allow for the incorporation of study-level covariates in an attempt to explain between-study heterogeneity and reduce inconsistency. Three possible model specifications assuming different assumptions are described and applied to a 17-treatment network for stroke prevention treatments in individuals with non-rheumatic atrial fibrillation.The paper demonstrates the feasibility of incorporating covariates within a mixed treatment comparison framework and using model fit statistics to choose between alternative model specifications. Although such an approach may adjust for inconsistencies in networks, as for standard meta-regression, the analysis will suffer from low power if the number of trials is small compared with the number of treatment comparators.