K. Jack Ishak

Meta-analysis of longitudinal studies

Background Longitudinal studies typically report estimates of the effect of a treatment or exposure at various times during the course of follow-up. Meta-analyses of these studies must account for correlations between effect estimates from the same study. Purpose To describe and contrast alternative approaches to handling correlations inherent to longitudinal effect estimates in meta-analyses. Methods. Linear mixed-effects models can account for correlations in a number of ways. We considered three alternatives: including study-specific random-effects, correlated time-specific random-effects or a general multivariate specification that also allows correlated within-study residuals. Data from a review of studies of the effect of deep-brain stimulation (DBS) in patients with Parkinsons disease are used to illustrate the application of these models. Results are contrasted with those from a naïve meta-analysis in which the correlations are ignored. Results The data included 46 studies that yielded 82 estimates of the effect of DBS measured at 3, 6, 12 months or later after implantation of the stimulator. Models that accounted for correlations, particularly the full multivariate specification, provided better fit (lower AIC) and yielded slightly more precise effect estimates. This was in part due to a relatively extreme observation from a study that provided similar estimates at other times, which in the naïve approach exerts greater influence since it is treated as an independent observation. Limitations Since the true values of the parameters are not known, it is impossible to confirm that estimates from the multivariate approach are necessarily more accurate. Conclusion Standard meta-analytic models can be readily extended to account for correlations between effects in longitudinal studies. These models may provide better fit and possibly more precise summary effect estimates. Clinical Trials 2007; 4: 525—539. http://ctj.sagepub.com

Cost Effectiveness of Donepezil in the Treatment of Mild to Moderate Alzheimer’s Disease

Background: Recommendations in the UK suggest restricting treatment of Alzheimer’s disease with cholinesterase inhibitors, on cost-effectiveness grounds, to patients with moderate cognitive decline. As the economic analyses that informed these recommendations have been the subject of debate, we sought to address the potential limitations of existing models and produce estimates of donepezil treatment cost effectiveness in the UK using the most recent available data and simulation techniques.Methods: A discrete-event simulation was developed that predicts progression of Alzheimer’s disease through correlated changes in cognition, behavioural disturbance and function. Patient-level data from seven randomized, placebo-controlled donepezil trials and a 7-year follow-up registry provided the basis for modeling longitudinal outcomes. Individuals in the simulation were assigned unique demographic and clinical characteristics and then followed for 10 years, with severity of disease tracked on continuous scales. Patient mix and costs were developed from UK-specific literature. Analyses were run for severity subgroups to evaluate outcomes for sub-populations with disease of mild versus moderate severity from both a healthcare payer and societal perspective. All costs are reported in £, year 2007 values, and all outcomes are discounted at 3.5% per annum.Results: Over 10 years, treatment of all patients with mild to moderate disease reduces overall direct medical costs by an average of over £2300 per patient. When unpaid caregiver time is also taken into consideration, savings increase to over £4700 per patient. Compared with untreated patients, patients receiving donepezil experience a discounted gain in QALYs averaging 0.11, with their caregivers gaining, on average, 0.01 QALYs. For the subset of patients starting treatment with more severe disease, savings are more modest, averaging about £1600 and £3750 from healthcare and societal perspectives, respectively. In probabilistic sensitivity analyses, donepezil dominated no treatment between 57% and 62% of replications when only medical costs were considered, and between 74% and 79% of replications when indirect costs were included, with results more favourable for treatment initiation in the mild versus moderate severity stages of the disease.Conclusions: Although the simulation results are not definitive, they suggest that donepezil leads to health benefits and cost savings when used to treat mild to moderately severe Alzheimer’s disease in the UK. They also indicate that both benefits and savings may be greatest when treatment is started while patients are still in the mild stages of Alzheimer’s disease.

Costs and cost‐effectiveness of carotid stenting versus endarterectomy for patients at increased surgical risk: Results from the SAPPHIRE trial

Objectives: To evaluate the cost‐effectiveness of carotid stenting vs. carotid endarterectomy using data from the SAPPHIRE trial. Background: Carotid stenting with embolic protection has been introduced as an alternative to carotid endarterectomy for prevention of cerebrovascular and cardiovascular events among patients at increased surgical risk. Methods: Between August 2000 and July 2002, 310 patients with an accepted indication for carotid endarterectomy but at high risk of complications were randomized to and subsequently underwent either carotid stenting (n = 159) or endarterectomy (n = 151). Clinical outcomes, resource use, costs, and quality of life were assessed prospectively for all patients over a 1‐year period. Life expectancy, quality‐adjusted life expectancy, and health care costs beyond the follow‐up period were estimated for patients alive at 1 year, based on observed clinical events during the first year of follow‐up. Results: Although initial procedural costs were significantly higher for stenting than for endarterectomy (mean difference:

No head-to-head trial? simulate the missing arms.

4,081/patient; 95% CI,

Canadian Economic Comparison of Extended-Release Oxybutynin and Immediate-Release Tolterodine in the Treatment of Overactive Bladder

3,849–

Do Bayesian adaptive trials offer advantages for comparative effectiveness research? Protocol for the RE-ADAPT study

4,355), mean post‐procedure length of stay was shorter for stenting (1.9 vs. 2.9 days; P < 0.001) with significant associated cost offsets. As a result, initial hospital costs were just

Accounting for the relationship between per diem cost and LOS when estimating hospitalization costs

559/patient higher with stenting (95% CI,

A Discrete-Event Simulation of Smoking-Cessation Strategies Based on Varenicline Pivotal Trial Data

3,470 less to

Adjusting for patient crossover in clinical trials using external data: a case study of lenalidomide for advanced multiple myeloma.

2,289 more). Neither follow‐up costs after discharge nor total 1‐year costs differed significantly. The incremental cost‐effectiveness ratio for stenting compared with endarterectomy was

889-3 Estimating life-years lost due to atherothrombotic events: Flexible survival functions for use in disease modeling

6,555 per quality‐adjusted life year (QALY) gained, with over 98 percent of bootstrap estimates <