Allan Wailoo

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.

The Effectiveness and Cost-Effectiveness of Donepezil, Galantamine, Rivastigmine and Memantine for the Treatment of Alzheimer's Disease (Review of Technology Appraisal No. 111): A Systematic Review and Economic Model

BACKGROUND Alzheimer’s disease (AD) is the most commonly occurring form of dementia. It is predominantly a disease of later life, affecting 5% of those over 65 in the UK. OBJECTIVES Review and update guidance to the NHS in England and Wales on the clinical effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine [acetylcholinesterase inhibitors (AChEIs)] and memantine within their licensed indications for the treatment of AD, which was issued in November 2006 (amended September 2007 and August 2009). DATA SOURCES Electronic databases were searched for systematic reviews and/or metaanalyses, randomised controlled trials (RCTs) and ongoing research in November 2009 and updated in March 2010; this updated search revealed no new includable studies. The databases searched included The Cochrane Library (2009 Issue 4, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials), MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PsycINFO, EconLit, ISI Web of Science Databases--Science Citation Index, Conference Proceedings Citation Index, and BIOSIS; the Centre for Reviews and Dissemination (CRD) databases--NHS Economic Evaluation Database, Health Technology Assessment, and Database of Abstracts of Reviews of Effects. REVIEW METHODS The clinical effectiveness systematic review was undertaken following the principles published by the NHS CRD. We included RCTs whose population was people with AD. The intervention and comparators depended on disease severity, measured by the Mini Mental State Examination (MMSE). INTERVENTIONS mild AD (MMSE 21-26)--donepezil, galantamine and rivastigmine; moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine and memantine; severe AD (MMSE < 10)--memantine. Comparators: mild AD (MMSE 21-26)--placebo or best supportive care (BSC); moderate AD (MMSE 10-20)--donepezil, galantamine, rivastigmine, memantine, placebo or BSC; severe AD (MMSE < 10)--placebo or BSC. The outcomes were clinical, global, functional, behavioural, quality of life, adverse events, costs and cost-effectiveness. Where appropriate, data were pooled using pair-wise meta-analysis, multiple outcome measures, metaregression and mixedtreatment comparisons. The decision model was based broadly on the structure of the three-state Markov model described in the previous technology assessment report, based upon time to institutionalisation, parameterised with updated estimates of effectiveness, costs and utilities. RESULTS Notwithstanding the uncertainty of our results, we found in the base case that the AChEIs are probably cost saving at a willingness-to-pay (WTP) of £’30,000 per qualityadjusted life-year (QALY) for people with mild-to-moderate AD. For this class of drugs, there is a > 99% probability that the AChEIs are more cost-effective than BSC. These analyses assume that the AChEIs have no effect on survival. For the AChEIs, in people with mild to moderate AD, the probabilistic sensitivity analyses suggested that donepezil is the most cost-effective, with a 28% probability of being the most cost-effective option at a WTP of £’30,000 per QALY (27% at a WTP of £’20,000 per QALY). In the deterministic results, donepezil dominates the other drugs and BSC, which, along with rivastigmine patches, are associated with greater costs and fewer QALYs. Thus, although galantamine has a slightly cheaper total cost than donepezil (£’69,592 vs £’69,624), the slightly greater QALY gains from donepezil (1.616 vs 1.617) are enough for donepezil to dominate galantamine.The probability that memantine is cost-effective in a moderate to severe cohort compared with BSC at a WTP of £’30,000 per QALY is 38% (and 28% at a WTP of £’20,000 per QALY). The deterministic ICER for memantine is £’32,100 per/QALY and the probabilistic ICER is £’36,700 per/QALY. LIMITATIONS Trials were of 6 months maximum follow-up, lacked reporting of key outcomes, provided no subgroup analyses and used insensitive measures. Searches were limited to English language, The model does not include behavioural symptoms and there is uncertainty about the model structure and parameters. CONCLUSIONS The additional clinical effectiveness evidence identified continues to suggest clinical benefit from the AChEIs in alleviating AD symptoms, although there is debate about the magnitude of the effect. Although there is also new evidence on the effectiveness of memantine, it remains less supportive of this drug’s use than the evidence for AChEIs. The conclusions concerning cost-effectiveness are quite different from the previous assessment. This is because both the changes in effectiveness and costs between drug use and non-drug use underlying the ICERs are very small. This leads to highly uncertain results, which are very sensitive to change. RESEARCH PRIORITIES: RCTs to include mortality, time to institutionalisation and quality of life, powered for subgroup analysis. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Tails from the Peak District: Adjusted Limited Dependent Variable Mixture Models of EQ-5D Questionnaire Health State Utility Values

OBJECTIVES Health utility data generated by using the EuroQol five-dimensional (EQ-5D) questionnaire are right bounded at 1 with a substantial gap to the next set of observations, left bounded, and multimodal. These features present challenges to the estimation of the effect of clinical and socioeconomic characteristics on health utilities. Our objective was to develop and demonstrate an appropriate method for dealing with these features. METHODS We developed a statistical model that incorporates an adjusted limited dependent variable approach to reflect the upper bound and the large gap in feasible EQ-5D questionnaire values. Further flexibility was then gained by adopting a mixture modeling framework to address the multimodality of the EQ-5D questionnaire distribution. We compared the performance of these approaches with that of those frequently adopted in the literature (linear and Tobit models) by using data from a clinical trial of patients with rheumatoid arthritis. RESULTS We found that three latent classes are appropriate in estimating EQ-5D questionnaire values from function, pain, and sociodemographic factors. Superior performance of the adjusted limited dependent variable mixture model was achieved in terms of Akaike and Bayesian information criteria, root mean square error, and mean absolute error. Unlike other approaches, the adjusted limited dependent variable mixture model fits the data well at high EQ-5D questionnaire levels and cannot predict unfeasible EQ-5D questionnaire values. CONCLUSIONS The distribution of the EQ-5D questionnaire is characterized by features that raise statistical challenges. It is well known that standard approaches do not perform well for this reason. This article developed an appropriate method to reflect these features by combining limited dependent variable and mixture modeling and demonstrated superior performance in a rheumatoid arthritis setting. Further refinement of the general framework and testing in other data sets are warranted. Analysis of utility data should apply methods that recognize the distributional features of the data.

Biologic drugs for rheumatoid arthritis in the Medicare program: a cost-effectiveness analysis.

OBJECTIVE Since the introduction of the Medicare Prescription Drug Improvement and Modernization Act and its associated demonstration project, coverage of selected biologic drugs has been expanded for Medicare beneficiaries. For rheumatoid arthritis, coverage was extended to etanercept, adalimumab, and anakinra in addition to the previously covered infliximab. We undertook to develop a model to compare the costs and quality-adjusted life years (QALYs) generated by each of the 4 biologic agents. METHODS Data were drawn from meta-analysis of randomized controlled trials and from a large longitudinal outcomes databank. Uncertainty was addressed using probabilistic and one-way sensitivity analyses. A lifetime horizon and Medicare viewpoint were adopted. RESULTS In the base case analysis, anakinra was the least effective and least costly strategy. Etanercept, adalimumab, and infliximab were similar in terms of effectiveness, but infliximab was more costly. If decision makers are willing to pay a maximum of

Assessing methods for dealing with treatment switching in randomised controlled trials: a simulation study

50,000/QALY, the probability that infliximab is cost-effective is <1%. Findings were robust to a range of sensitivity analyses. Only if the dose of infliximab remains constant over time is this likely to be a cost-effective strategy. CONCLUSION Infliximab is unlikely to be cost-effective in the Medicare population compared with either etanercept or adalimumab. Anakinra is substantially less costly but is also less effective than the 3 tumor necrosis factor alpha inhibitors.

Utilities versus Rights to Publicly Provided Goods: Arguments and Evidence from Health Care Rationing

BackgroundWe investigate methods used to analyse the results of clinical trials with survival outcomes in which some patients switch from their allocated treatment to another trial treatment. These included simple methods which are commonly used in medical literature and may be subject to selection bias if patients switching are not typical of the population as a whole. Methods which attempt to adjust the estimated treatment effect, either through adjustment to the hazard ratio or via accelerated failure time models, were also considered. A simulation study was conducted to assess the performance of each method in a number of different scenarios.Results16 different scenarios were identified which differed by the proportion of patients switching, underlying prognosis of switchers and the size of true treatment effect. 1000 datasets were simulated for each of these and all methods applied. Selection bias was observed in simple methods when the difference in survival between switchers and non-switchers were large. A number of methods, particularly the AFT method of Branson and Whitehead were found to give less biased estimates of the true treatment effect in these situations.ConclusionsSimple methods are often not appropriate to deal with treatment switching. Alternative approaches such as the Branson & Whitehead method to adjust for switching should be considered.

Weighting Must Wait: Incorporating Equity Concerns into Cost-Effectiveness Analysis May Take Longer than Expected

This paper challenges the QALY maximizing approach to rationing health care on the grounds of the consequentialist (and sometimes approximately utilitarian) moral framework on which it is based. An alternative methodological approach is suggested and, in addition to consequences, four normative determinants of health care entitlements are identified: rights, public opinion, social contracts and community values. Survey evidence is presented which shows support for these alternative frameworks and a rejection of consequentialism. The paper suggests that a (if not the) major challenge facing the designers of rationing guidelines is that of pluralism, i.e. the need to integrate considerations from a set of frameworks.

Cluster randomized controlled trial of the effectiveness of audit and feedback and educational outreach on improving nursing practice and patient outcomes.

Current practice in economic evaluation is to assign equal social value to a unit of health improvement (‘a QALY is a QALY is a QALY’). Alternative equity positions are typically considered separately from efficiency. One proposal seeks to integrate these two sets of societal concerns by attaching equity weights to QALYs. To date, research in pursuit of this goal has focussed on candidate equity criteria and methods for estimating such weights. It has implicitly been assumed that should legitimate, valid and reliable equity weights become available, it would be a straightforward task to incorporate them as a separate simple calculation after estimating cost per un-weighted QALY. This article suggests that, in many situations, these simple approaches to incorporating equity weights will not appropriately reflect the preferences on which the weights are based and that the appropriate incorporation of equity weights in cost-effectiveness analyses will be technically challenging. In addition to the technical challenges, there are a number of issues that arise in the movement from implicit to explicit consideration of equity. Whilst equity weights can, conceptually, be incorporated in economic evaluation, there are a number of challenges to be addressed before the results of such analyses can be considered robust and a fit basis for resource allocation decisions.

A systematic review of molecular and biological markers in tumours of the Ewing's sarcoma family

Background:Current understanding of implementation methods is limited, and research has focused on changing doctors’ behaviors. Aim:Our aim was to evaluate the impact of audit and feedback and educational outreach in improving nursing practice and patient outcomes. Methods:Using a factorial design, cluster randomized controlled trial, we evaluated 194 community nurses in 157 family practices and 1078 patients with diagnosis of urinary incontinence (UI) for nurses compliance with evidence-linked review criteria for the assessment and management of UI and impact on psychologic and social well-being and symptoms. In the outreach arms, nurses’ self-reported barriers informed development of tailored strategies. Results:In comparison with educational materials alone, the implementation methods tested did not improve care at 6 months follow-up. Moderate rates of improvement (10–17% of patients) in performance for the assessment of UI and greater rates of improvement (20–30% of patients) for the management of care were found but effects were similar across arms. Improvement in patient outcomes was more consistently positive for educational outreach than for audit and feedback but differences were not significant. Adjustment for caseload size, severity or duration of UI and patients’ age did not alter results. Conclusions:Printed educational materials alone may be as effective as audit and feedback and educational outreach in improving nurses’ performance and outcomes of care for people with UI. Greater understanding of the underlying processes in improving performance within multidisciplinary teams through further, theory-driven studies with “no intervention” control groups and longer follow-up are needed.

The effectiveness of anti-TNF-alpha therapies when used sequentially in rheumatoid arthritis patients: a systematic review and meta-analysis.

The aims of this study were to perform the first systematic review of molecular and biological tumour markers in tumours of the Ewings sarcoma family (ESFT), and evaluate the current evidence for their clinical use. A well-defined, reproducible search strategy was used to identify the relevant literature from 1966 to February 2000. Papers were independently assessed for tumour markers used in the screening, diagnosis, prognosis or monitoring of patients with ESFT. Eighty-four papers studying the use of 70 different tumour markers in ESFTs were identified. Low-quality, inconsistent reporting limited meta-analysis to that of prognostic data for 28 markers. Patients with tumours lacking S-100 protein expression have a better overall survival (OS) (hazard ratio (HR)=0.41, 95% confidence interval (CI) 0.19, 0.89) than those with expression; patients with high levels of serum LDH had a worse OS and disease-free survival (DFS) (OS: HR=2.92, CI 2.16, 3.94, DFS: HR=3.38, 95% CI 2.28, 4.99); patients with localised disease and tumours expressing type 1 EWS-FLI1 fusion transcripts had an improved DFS compared with those with other fusion transcript types (HR=0.17, 95% CI 0.079, 0.37). The knowledge base formed should facilitate more informative future research. Improved statistical reporting and large, multicentre prospective studies are advocated.