Model-observational bridging study on the effectiveness of ezetimibe on cardiovascular morbidity and mortality in France: A population-based study.

BACKGROUND: To evaluate the real-life impact of ezetimibe on cardiovascular (CV) morbidity and mortality in France. OBJECTIVE: To estimate the number of non-fatal and fatal CV events that could be prevented and corresponding number of patients needed to treat (NNT) with ezetimibe to prevent one CV event over 5 years. METHODS: Non-interventional 48-month follow-up cohort conducted in hypercholesterolemic patients starting on ezetimibe <3 months at study entry, either as monotherapy or combined with statins. Prediction modeling using discrete event simulation with calibrated Framingham CV risk equations was applied to data from pivotal clinical trials on ezetimibe and real-life data derived from the cohort. RESULTS: A total of 3215 patients in the cohort accumulated 9314 person-years of follow-up for an average of 2.9 years. Mean age was 61.5 (standard deviation [SD] = 10.7), 54.6% were males, and 27.0% had a history of CV disease. Baseline LDL-cholesterol averaged 4.1 mmol/L (159 mg/dL; SD = 1.0) and HDL-C 1.6 mmol/L (62 mg/dL; SD = 0.5). LDL-C decreased in the first 12 months in ezetimibe-LLT (lipid-lowering therapy) initiators, switchers (monotherapy), and combination therapy with a statin by respectively 21.3%, 6.4%, and 29.1%. The corresponding predicted rate reductions of CV events (non-fatal and fatal) compared to no treatment or to a statin (combination therapy) were respectively 8, 2, and 12 per 1000 patients treated over 5 years, with a global NNT of 143 patients over 5 years. CONCLUSION: These results, accounting for observed CV event rates, risk factors evolution over time and adherence to treatment in real life, were consistent with those from clinical trials.

Systematic Review of Model-Based Economic Evaluations of Treatments for Alzheimer's Disease.

BACKGROUND: Numerous economic evaluations using decision-analytic models have assessed the cost effectiveness of treatments for Alzheimer's disease (AD) in the last two decades. It is important to understand the methods used in the existing models of AD and how they could impact results, as they could inform new model-based economic evaluations of treatments for AD. OBJECTIVE: The aim of this systematic review was to provide a detailed description on the relevant aspects and components of existing decision-analytic models of AD, identifying areas for improvement and future development, and to conduct a quality assessment of the included studies. METHODS: We performed a systematic and comprehensive review of cost-effectiveness studies of pharmacological treatments for AD published in the last decade (January 2005 to February 2015) that used decision-analytic models, also including studies considering patients with mild cognitive impairment (MCI). The background information of the included studies and specific information on the decision-analytic models, including their approach and components, assumptions, data sources, analyses, and results, were obtained from each study. A description of how the modeling approaches and assumptions differ across studies, identifying areas for improvement and future development, is provided. At the end, we present our own view of the potential future directions of decision-analytic models of AD and the challenges they might face. RESULTS: The included studies present a variety of different approaches, assumptions, and scope of decision-analytic models used in the economic evaluation of pharmacological treatments of AD. The major areas for improvement in future models of AD are to include domains of cognition, function, and behavior, rather than cognition alone; include a detailed description of how data used to model the natural course of disease progression were derived; state and justify the economic model selected and structural assumptions and limitations; provide a detailed (rather than high-level) description of the cost components included in the model; and report on the face-, internal-, and cross-validity of the model to strengthen the credibility and confidence in model results. The quality scores of most studies were rated as fair to good (average 87.5, range 69.5-100, in a scale of 0-100). CONCLUSION: Despite the advancements in decision-analytic models of AD, there remain several areas of improvement that are necessary to more appropriately and realistically capture the broad nature of AD and the potential benefits of treatments in future models of AD.

Cost-utility analysis of memantine extended release added to cholinesterase inhibitors compared to cholinesterase inhibitor monotherapy for the treatment of moderate-to-severe dementia of the Alzheimer's type in the US.

OBJECTIVE: This study evaluates the cost-effectiveness of memantine extended release (ER) as an add-on therapy to acetylcholinesterase inhibitor (AChEI) [combination therapy] for treatment of patients with moderate-to-severe Alzheimer's disease (AD) from both a healthcare payer and a societal perspective over 3 years when compared to AChEI monotherapy in the US. METHODS: A phase III trial evaluated the efficacy and safety of memantine ER for treatment of AD patients taking an AChEI. The analysis assessed the long-term costs and health outcomes using an individual patient simulation in which AD progression is modeled in terms of cognition, behavior, and functioning changes. Input parameters are based on patient-level trial data, published literature, and publicly available data sources. Changes in anti-psychotic medication use are incorporated based on a published retrospective cohort study. Costs include drug acquisition and monitoring, total AD-related medical care, and informal care associated with caregiver time. Incremental cost-utility ratio (ICUR), life years, care time for caregiver, time in community and institution, time on anti-psychotics, time by disease severity, and time without severe symptoms are reported. Costs and health outcomes are discounted at 3% per annum. RESULTS: Considering a societal perspective over 3 years, this analysis shows that memantine ER combined with an AChEI provides better clinical outcomes and lower costs than AChEI monotherapy. Discounted average savings were estimated at $18,355 and $20,947 per patient and quality-adjusted life-years (QALYs) increased by an average of 0.12 and 0.13 from a societal and healthcare payer perspective, respectively. Patients on combination therapy spent an average of 4 months longer living at home and spend less time in moderate-severe and severe stages of the disease. CONCLUSION: Combination therapy for patients with moderate-to-severe AD is a cost-effective treatment compared to AChEI monotherapy in the US.

Evaluating disease-modifying agents: a simulation framework for Alzheimer's disease.

BACKGROUND: Considerable advances have been made in modeling Alzheimer's disease (AD), with a move towards individual-level rather than cohort models and simulations that consider multiple dimensions when evaluating disease severity. However, the possibility that disease-modifying agents (DMAs) may emerge requires an update of existing modeling frameworks. OBJECTIVES: The aim of this study was to develop a simulation allowing for economic evaluation of DMAs in AD. METHODS: The model was developed based on a previously published, well-validated, discrete event simulation which measures disease severity on the basis of cognition, behaviour, and function, and captures the interrelated changes in these measures for individuals. The updated model adds one more domain, patient dependence, in addition to cognition, behaviour, and function to better characterize disease severity. Furthermore, the model was modified to have greater flexibility in assessing the impact of various important assumptions, such as the long-term effectiveness of DMAs and their impact on survival, on model outcomes. A validation analysis was performed to examine how well the model predicted change in disease severity among patients not receiving DMA treatment by comparing model results to those observed in two recent phase III clinical trials of bapineuzumab. In addition, various hypothetical scenarios were tested to demonstrate the improved features of the model. RESULTS: Validation results show that the model closely predicts the mean changes in disease severity over 18 months. Results from different hypothetical scenarios show that the model allows for credible assessment of those major uncertainties surrounding the long-term effectiveness of DMAs, including the potential impact of improved survival with DMA treatment. They also indicate that varying these assumptions could have a major impact on the value of DMAs. CONCLUSIONS: The updated economic model has good predictive power, but validation against longer-term outcomes is still needed. Our analyses also demonstrate the importance of designing a model with sufficient flexibility such that the model allows for assessment of the impact of key sources of uncertainty on the value of DMAs.

Economic implications of using bendamustine, alemtuzumab, or chlorambucil as a first-line therapy for chronic lymphocytic leukemia in the US: a cost-effectiveness analysis.

BACKGROUND: The objective of this analysis was to evaluate the cost-effectiveness of using bendamustine versus alemtuzumab or bendamustine versus chlorambucil as a first-line therapy in patients with Binet stage B or C chronic lymphocytic leukemia (CLL) in the US. METHODS: A discrete event simulation of the disease course of CLL was developed to evaluate the economic implications of single-agent treatment with bendamustine, alemtuzumab, or chlorambucil, which are indicated for a treatment-naïve patient population with Binet stage B or C CLL. Data from clinical trials were used to create a simulated patient population, risk equations for progression-free survival and survival post disease progression, response rates, and rates of adverse events. Costs from a US health care payer perspective in 2012 US dollars, survival (life years), and quality-adjusted life years (QALYs) were estimated over a patient's lifetime; all were discounted at 3% per year. RESULTS: Compared with alemtuzumab, bendamustine was considered to be a dominant treatment providing greater benefit (6.10 versus 5.37 life years and 4.02 versus 3.45 QALYs) at lower cost ($78,776 versus $121,441). Compared with chlorambucil, bendamustine was associated with higher costs ($78,776 versus $42,337) but with improved health outcomes (6.10 versus 5.21 life years and 4.02 versus 3.30 QALYs), resulting in incremental cost-effectiveness ratios of $40,971 per life year gained and $50,619 per QALY gained. CONCLUSION: Bendamustine is expected to provide cost savings and greater health benefit than alemtuzumab in treatment-naïve patients with CLL. Furthermore, it can be considered as a cost-effective treatment providing health benefits at an acceptable cost versus chlorambucil in the US.

Smoking cessation treatment and outcomes patterns simulation: a new framework for evaluating the potential health and economic impact of smoking cessation interventions.

BACKGROUND: Most existing models of smoking cessation treatments have considered a single quit attempt when modelling long-term outcomes. OBJECTIVE: To develop a model to simulate smokers over their lifetimes accounting for multiple quit attempts and relapses which will allow for prediction of the long-term health and economic impact of smoking cessation strategies. METHODS: A discrete event simulation (DES) that models individuals' life course of smoking behaviours, attempts to quit, and the cumulative impact on health and economic outcomes was developed. Each individual is assigned one of the available strategies used to support each quit attempt; the outcome of each attempt, time to relapses if abstinence is achieved, and time between quit attempts is tracked. Based on each individual's smoking or abstinence patterns, the risk of developing diseases associated with smoking (chronic obstructive pulmonary disease, lung cancer, myocardial infarction and stroke) is determined and the corresponding costs, changes to mortality, and quality of life assigned. Direct costs are assessed from the perspective of a comprehensive US healthcare payer ($US, 2012 values). Quit attempt strategies that can be evaluated in the current simulation include unassisted quit attempts, brief counselling, behavioural modification therapy, nicotine replacement therapy, bupropion, and varenicline, with the selection of strategies and time between quit attempts based on equations derived from survey data. Equations predicting the success of quit attempts as well as the short-term probability of relapse were derived from five varenicline clinical trials. RESULTS: Concordance between the five trials and predictions from the simulation on abstinence at 12 months was high, indicating that the equations predicting success and relapse in the first year following a quit attempt were reliable. Predictions allowing for only a single quit attempt versus unrestricted attempts demonstrate important differences, with the single quit attempt simulation predicting 19 % more smoking-related diseases and 10 % higher costs associated with smoking-related diseases. Differences are most prominent in predictions of the time that individuals abstain from smoking: 13.2 years on average over a lifetime allowing for multiple quit attempts, versus only 1.2 years with single quit attempts. Differences in abstinence time estimates become substantial only 5 years into the simulation. In the multiple quit attempt simulations, younger individuals survived longer, yet had lower lifetime smoking-related disease and total costs, while the opposite was true for those with high levels of nicotine dependence. CONCLUSION: By allowing for multiple quit attempts over the course of individuals' lives, the simulation can provide more reliable estimates on the health and economic impact of interventions designed to increase abstinence from smoking. Furthermore, the individual nature of the simulation allows for evaluation of outcomes in populations with different baseline profiles. DES provides a framework for comprehensive and appropriate predictions when applied to smoking cessation over smoker lifetimes.

Improved perioperative blood pressure control leads to reduced hospital costs.

BACKGROUND: Perioperative hypertension affects 80% of cardiac surgery patients and is associated with an increased risk of complications. OBJECTIVE: To determine the relationship between perioperative blood pressure (BP) control and hospital costs for cardiac surgery in the United States (US) and estimate the potential cost reductions associated with effective therapies. METHODS: The analysis estimated hospitalization costs (2011 US dollars (USD)) for cardiac surgery when BP was controlled with intravenous (IV) antihypertensives. Patient characteristics, hospital length of stay, and clinical event rates during the initial hospitalization and post-discharge 30 days after study drug infusion were based on the ECLIPSE (Evaluation of CLevidipine In the Perioperative Treatment of Hypertension Assessing Safety Events) trials. These clinical trial data were combined with data from the Massachusetts Acute Hospital Case Mix Database 2007 - 2009 (MA Case Mix Database) to estimate total hospitalization costs. RESULTS: Effective perioperative BP control in patients requiring IV antihypertensives was associated with a 7% decrease in hospital costs compared with less effective BP control. Reductions in total hospital costs associated with clevidipine versus other IV antihypertensives averaged $394 per patient overall. Cost savings with clevidipine exceeded $500 per patient versus sodium nitroprusside and nitroglycerin, but only $22 compared to nicardipine. CONCLUSION: Improved perioperative BP control may reduce hospital costs. Given the low cost of IV antihypertensives, the total hospital cost reductions may offset any incremental cost increases associated with newer, more effective therapies.

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

BACKGROUND: Hospitalization costs in clinical trials are typically derived by multiplying the length of stay (LOS) by an average per-diem (PD) cost from external sources. This assumes that PD costs are independent of LOS. Resource utilization in early days of the stay is usually more intense, however, and thus, the PD cost for a short hospitalization may be higher than for longer stays. The shape of this relationship is unlikely to be linear, as PD costs would be expected to gradually plateau. This paper describes how to model the relationship between PD cost and LOS using flexible statistical modelling techniques. METHODS: An example based on a clinical study of clevidipine for the treatment of peri-operative hypertension during hospitalizations for cardiac surgery is used to illustrate how inferences about cost-savings associated with good blood pressure (BP) control during the stay can be affected by the approach used to derive hospitalization costs.Data on the cost and LOS of hospitalizations for coronary artery bypass grafting (CABG) from the Massachusetts Acute Hospital Case Mix Database (the MA Case Mix Database) were analyzed to link LOS to PD cost, factoring in complications that may have occurred during the hospitalization or post-discharge. The shape of the relationship between LOS and PD costs in the MA Case Mix was explored graphically in a regression framework. A series of statistical models including those based on simple logarithmic transformation of LOS to more flexible models using LOcally wEighted Scatterplot Smoothing (LOESS) techniques were considered. A final model was selected, using simplicity and parsimony as guiding principles in addition traditional fit statistics (like Akaike's Information Criterion, or AIC). This mapping was applied in ECLIPSE to predict an LOS-specific PD cost, and then a total cost of hospitalization. These were then compared for patients who had good vs. poor peri-operative blood-pressure control. RESULTS: The MA Case Mix dataset included data from over 10,000 patients. Visual inspection of PD vs. LOS revealed a non-linear relationship. A logarithmic model and a series of LOESS and piecewise-linear models with varying connection points were tested. The logarithmic model was ultimately favoured for its fit and simplicity. Using this mapping in the ECLIPSE trials, we found that good peri-operative BP control was associated with a cost savings of $5,366 when costs were derived using the mapping, compared with savings of $7,666 obtained using the traditional approach of calculating the cost. CONCLUSIONS: PD costs vary systematically with LOS, with short stays being associated with high PD costs that drop gradually and level off. The shape of the relationship may differ in other settings. It is important to assess this and model the observed pattern, as this may have an impact on conclusions based on derived hospitalization costs.

Inclusion of compliance and persistence in economic models: past, present and future.

Economic models are developed to provide decision makers with information related to the real-world effectiveness of therapeutics, screening and diagnostic regimens. Although compliance with these regimens often has a significant impact on real-world clinical outcomes and costs, compliance and persistence have historically been addressed in a relatively superficial fashion in economic models. In this review, we present a discussion of the current state of economic modelling as it relates to the consideration of compliance and persistence. We discuss the challenges associated with the inclusion of compliance and persistence in economic models and provide an in-depth review of recent modelling literature that considers compliance or persistence, including a brief summary of previous reviews on this topic and a survey of published models from 2005 to 2012. We review the recent literature in detail, providing a therapeutic-area-specific discussion of the approaches and conclusions drawn from the inclusion of compliance or persistence in economic models. In virtually all publications, variation of model parameters related to compliance and persistence was shown to have a significant impact on predictions of economic outcomes. Growing recognition of the importance of compliance and persistence in the context of economic evaluations has led to an increasing number of economic models that consider these factors, as well as the use of more sophisticated modelling techniques such as individual simulations that provide an avenue for more rigorous consideration of compliance and persistence than is possible with more traditional methods. However, we note areas of continuing concern cited by previous reviews, including inconsistent definitions, documentation and tenuous assumptions required to estimate the effect of compliance and persistence. Finally, we discuss potential means to surmount these challenges via more focused efforts to collect compliance and persistence data.

Evaluating the cost effectiveness of donepezil in the treatment of Alzheimer's disease in Germany using discrete event simulation.

BACKGROUND: Previous cost-effectiveness studies of cholinesterase inhibitors have modeled Alzheimer's disease (AD) progression and treatment effects through single or global severity measures, or progression to "Full Time Care". This analysis evaluates the cost-effectiveness of donepezil versus memantine or no treatment in Germany by considering correlated changes in cognition, behavior and function. METHODS: Rates of change were modeled using trial and registry-based patient level data. A discrete event simulation projected outcomes for three identical patient groups: donepezil 10 mg, memantine 20 mg and no therapy. Patient mix, mortality and costs were developed using Germany-specific sources. RESULTS: Treatment of patients with mild to moderately severe AD with donepezil compared to no treatment was associated with 0.13 QALYs gained per patient, and 0.01 QALYs gained per caregiver and resulted in average savings of €7,007 and €9,893 per patient from the healthcare system and societal perspectives, respectively. In patients with moderate to moderately-severe AD, donepezil compared to memantine resulted in QALY gains averaging 0.01 per patient, and savings averaging €1,960 and €2,825 from the healthcare system and societal perspective, respectively.In probabilistic sensitivity analyses, donepezil dominated no treatment in most replications and memantine in over 70% of the replications. Donepezil leads to savings in 95% of replications versus memantine. CONCLUSIONS: Donepezil is highly cost-effective in patients with AD in Germany, leading to improvements in health outcomes and substantial savings compared to no treatment. This holds across a variety of sensitivity analyses.

Florbetaben PET in the Early Diagnosis of Alzheimer's Disease: A Discrete Event Simulation to Explore Its Potential Value and Key Data Gaps.

The growing understanding of the use of biomarkers in Alzheimer's disease (AD) may enable physicians to make more accurate and timely diagnoses. Florbetaben, a beta-amyloid tracer used with positron emission tomography (PET), is one of these diagnostic biomarkers. This analysis was undertaken to explore the potential value of florbetaben PET in the diagnosis of AD among patients with suspected dementia and to identify key data that are needed to further substantiate its value. A discrete event simulation was developed to conduct exploratory analyses from both US payer and societal perspectives. The model simulates the lifetime course of disease progression for individuals, evaluating the impact of their patient management from initial diagnostic work-up to final diagnosis. Model inputs were obtained from specific analyses of a large longitudinal dataset from the New England Veterans Healthcare System and supplemented with data from public data sources and assumptions. The analyses indicate that florbetaben PET has the potential to improve patient outcomes and reduce costs under certain scenarios. Key data on the use of florbetaben PET, such as its influence on time to confirmation of final diagnosis, treatment uptake, and treatment persistency, are unavailable and would be required to confirm its value.

Discrete event simulation: the preferred technique for health economic evaluations?

OBJECTIVES: To argue that discrete event simulation should be preferred to cohort Markov models for economic evaluations in health care. METHODS: The basis for the modeling techniques is reviewed. For many health-care decisions, existing data are insufficient to fully inform them, necessitating the use of modeling to estimate the consequences that are relevant to decision-makers. These models must reflect what is known about the problem at a level of detail sufficient to inform the questions. Oversimplification will result in estimates that are not only inaccurate, but potentially misleading. RESULTS: Markov cohort models, though currently popular, have so many limitations and inherent assumptions that they are inadequate to inform most health-care decisions. An event-based individual simulation offers an alternative much better suited to the problem. A properly designed discrete event simulation provides more accurate, relevant estimates without being computationally prohibitive. It does require more data and may be a challenge to convey transparently, but these are necessary trade-offs to provide meaningful and valid results. CONCLUSION: In our opinion, discrete event simulation should be the preferred technique for health economic evaluations today.

Cost effectiveness of donepezil in the treatment of mild to moderate Alzheimer's disease: a UK evaluation using discrete-event simulation.

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. 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 pound, year 2007 values, and all outcomes are discounted at 3.5% per annum. Over 10 years, treatment of all patients with mild to moderate disease reduces overall direct medical costs by an average of over pound2300 per patient. When unpaid caregiver time is also taken into consideration, savings increase to over pound4700 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 pound1600 and pound3750 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. 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.

Adult vaccination strategies for the control of pertussis in the United States: an economic evaluation including the dynamic population effects.

BACKGROUND: Prior economic evaluations of adult and adolescent vaccination strategies against pertussis have reached disparate conclusions. Using static approaches only, previous studies failed to analytically include the indirect benefits derived from herd immunity as well as the impact of vaccination on the evolution of disease incidence over time. METHODS: We assessed the impact of different pertussis vaccination strategies using a dynamic compartmental model able to consider pertussis transmission. We then combined the results with economic data to estimate the relative cost-effectiveness of pertussis immunization strategies for adolescents and adults in the US. The analysis compares combinations of programs targeting adolescents, parents of newborns (i.e. cocoon strategy), or adults of various ages. RESULTS: In the absence of adolescent or adult vaccination, pertussis incidence among adults is predicted to more than double in 20 years. Implementing an adult program in addition to childhood and adolescent vaccination either based on 1) a cocoon strategy and a single booster dose or 2) a decennial routine vaccination would maintain a low level of pertussis incidence in the long run for all age groups (respectively 30 and 20 cases per 100,000 person years). These strategies would also result in significant reductions of pertussis costs (between -77% and -80% including additional vaccination costs). The cocoon strategy complemented by a single booster dose is the most cost-effective one, whereas the decennial adult vaccination is slightly more effective in the long run. CONCLUSIONS: By providing a high level of disease control, the implementation of an adult vaccination program against pertussis appears to be highly cost-effective and often cost-saving.

NICE cost-effectiveness appraisal of cholinesterase inhibitors: was the right question posed? Were the best tools used?

The National Institute for Health and Clinical Excellence (NICE) recently issued updated guidance on the use of cholinesterase inhibitors in the treatment of Alzheimer's disease. NICE initially recommended that cholinesterase inhibitors no longer be used, but final guidance restricted treatment to patients with disease of a moderately severe stage. This decision was based largely on results from a heavily criticised economic evaluation that used an adaptation of the Assessment of Health Economics in Alzheimer's Disease (AHEAD) model. As the developers of the AHEAD model, we examined the appropriateness of NICE's economic analyses and presentation of results. We attempted to replicate NICE's results by modifying the original AHEAD model. Sensitivity analyses were then run using the modified AHEAD model to evaluate the extent of uncertainty in predictions. The AHEAD(NICE) analyses resulted in an incremental cost-effectiveness ratio for galantamine of 82,000 pound per QALY gained (year 2003 values) from the perspective of the UK NHS and Personal Social Services. This was later revised to 46,000 pound per QALY, compared with < 9000 pound per discounted QALY gained (year 2001 values) in the original AHEAD model. Using our modified AHEAD with effectiveness estimates matching those of AHEAD(NICE), we show that NICE's choice and presentation of sensitivity analyses obscured the instability of their estimates. In the final NICE evaluation, the recommendation to delay treatment with cholinesterase inhibitors until patients have moderately severe disease was based on critical assumptions in the economic analyses that had little evidence to support them. The case of NICE's guidance on cholinesterase inhibitors highlights the importance of transparent and valid economic evaluations and the dangers of using inappropriate modelling technologies, basing analyses on a limited subset of the available data, and insufficiently reflecting the uncertainty in estimates that are intended to inform decision makers.

Invasive meningococcal disease epidemiology and control measures: a framework for evaluation.

BACKGROUND: Meningococcal disease can have devastating consequences. As new vaccines emerge, it is necessary to assess their impact on public health. In the absence of long-term real world data, modeling the effects of different vaccination strategies is required. Discrete event simulation provides a flexible platform with which to conduct such evaluations. METHODS: A discrete event simulation of the epidemiology of invasive meningococcal disease was developed to quantify the potential impact of implementing routine vaccination of adolescents in the United States with a quadrivalent conjugate vaccine protecting against serogroups A, C, Y, and W-135. The impact of vaccination is assessed including both the direct effects on individuals vaccinated and the indirect effects resulting from herd immunity. The simulation integrates a variety of epidemiologic and demographic data, with core information on the incidence of invasive meningococcal disease and outbreak frequency derived from data available through the Centers for Disease Control and Prevention. Simulation of the potential indirect benefits of vaccination resulting from herd immunity draw on data from the United Kingdom, where routine vaccination with a conjugate vaccine has been in place for a number of years. Cases of disease are modeled along with their health consequences, as are the occurrence of disease outbreaks. RESULTS: When run without a strategy of routine immunization, the simulation accurately predicts the age-specific incidence of invasive meningococcal disease and the site-specific frequency of outbreaks in the Unite States. 2,807 cases are predicted annually, resulting in over 14,000 potential life years lost due to invasive disease. In base case analyses of routine vaccination, life years lost due to infection are reduced by over 45% (to 7,600) when routinely vaccinating adolescents 12 years of age at 70% coverage. Sensitivity analyses indicate that herd immunity plays an important role when this population is targeted for vaccination. While 1,100 cases are avoided annually when herd immunity effects are included, in the absence of any herd immunity, the number of cases avoided with routine vaccination falls to 380 annually. The duration of vaccine protection also strongly influences results. CONCLUSION: In the absence of appropriate real world data on outcomes associated with large-scale vaccination programs, decisions on optimal immunization strategies can be aided by discrete events simulations such as the one described here. Given the importance of herd immunity on outcomes associated with routine vaccination, published estimates of the economic efficiency of routine vaccination with a quadrivalent conjugate vaccine in the United States may have considerably underestimated the benefits associated with a policy of routine immunization of adolescents.

Managing meningococcal disease in the United States: Hospital case characteristics and costs by age.

OBJECTIVE: Meningococcal disease occurs worldwide. Approximately 1400 to 2800 cases are reported in the United States annually. The goal of this analysis was to examine hospitalized cases of meningitis and meningococcemia to identify case characteristics, resource use, and inpatient care costs. METHODS: International Classification of Diseases-9th Revision-Clinical Modification diagnosis codes 036.0-036.9 were used to identify cases from roughly 1000 hospitals in four all payer state discharge databases. Multiyear data (1999-2001) were examined to identify demographics, admission month, health service utilization, and hospital costs by age group: infant (<1 years), children (1-10 years), adolescent (11-17 years), young adult (18-22 years), adults (23-49 years), and adults (> or =50 years). Cost estimates include accommodations, ancillary and physician services, reported in 2003 US dollars. RESULTS: Of 1654 cases of meningococcal disease identified, meningococcemia was coded for 51%. Adults accounted for 33% of the cases. The highest rate of admissions occurred from January through March and 62% were admitted via the Emergency Department. Inpatient case fatality rate was 6.4%; 71% of those who died had meningococcemia. The mean length of stay was 9 days. Of survivors, 91% were discharged home (1% with intravenous medications and 11% with other home health-care services) while 7% required further subacute inpatient care. The average cost per hospitalization was estimated at 23,294 dollars per patient. Infants had the lowest average cost per stay (16,793 dollars) and adolescents had the highest (28,202 dollars). CONCLUSIONS: The presence of meningococcemia results in a greater death rate, longer length of stay, and increased care costs. Meningococcal disease has substantial economic, as well as profound clinical consequences for patients of all ages.

Pharmacological management of overactive bladder : a systematic and critical review of published economic evaluations.

Overactive bladder is a common condition, with recent findings estimating the prevalence in adults at about 15%. Symptoms, including urinary urgency, high voiding frequency and urge incontinence, have been shown to decrease patients' quality of life. Given its high prevalence, the economic burden of overactive bladder is also substantial, with a recent estimate placing the annual cost in the US at 9.1 billion US dollars (year 2000 values). The objective of this review is to provide a critical appraisal of published economic evaluations of pharmacological and non-pharmacological treatments for overactive bladder. Published economic evaluations of treatments for overactive bladder have focused entirely on pharmacological treatments -- mainly on the two most commonly used drugs, oxybutynin and tolterodine, each of which is available in immediate- and extended-release formulations. Ten economic evaluations (more than half are cost-effectiveness studies) have been published. Modelling with decision trees or Markov models has been the predominant method. Evaluations comparing drug therapy with no treatment have concluded that drug therapy is cost effective. Analyses comparing the formulations of oxybutynin and tolterodine have produced highly inconsistent results, largely due to the sources of data employed for effectiveness and treatment discontinuation rates. There are no evaluations of drugs relative to non-pharmacological treatment, and there are other significant gaps in the economic evaluations of treatment to date. These include gaps resulting from a lack of reliable data on the performance of these drugs in real-world settings, particularly data on long-term persistence with treatment. A more definitive pharmacoeconomic comparison of oxybutynin and tolterodine formulations, incorporating all available clinical data, and other treatment options would help direct treatment.