The lifetime health and economic burden of obesity in five European countries: what is the potential impact of prevention?

AIM: Estimating the burden of obesity in five European countries (Germany, Greece, the Netherlands, Spain and the UK) and the potential health benefits and changes in health care costs associated with a reduction in body mass index (BMI). MATERIALS AND METHODS: A Markov model was used to estimate the long-term burden of obesity. Health states were based on the occurrence of diabetes, ischaemic heart disease and stroke. Multiple registries and literature sources were used to derive the demographic, epidemiological and cost input parameters. For the base-case analyses, the model was run for a starting cohort of healthy obese people with a BMI of 30 and 35 kg/m2 aged 40 years to estimate the lifetime impact of obesity and the impact of a one-unit decrease in BMI. Different scenario and sensitivity analyses were performed. RESULTS: The base-case analyses showed that total lifetime health care costs (for obese people aged 40 and BMI 35 kg/m2 ) ranged from €75 376 in Greece to €343 354 in the Netherlands, with life expectancies ranging from 37.9 years in Germany to 39.7 years in Spain. A one-unit decrease in BMI showed gains in life expectancy ranging from 0.65 to 0.68 year and changes in total health care costs varying from -€1563 to +€4832. CONCLUSIONS: The economic burden of obesity is substantial in the five countries. Decreasing BMI results in health gains, reductions in obesity-related health care costs, but an increase in non-obesity related health care costs, which emphasizes the relevance of including all costs in decision making on implementation of preventive interventions.

Performance of the EQ-5D-5L Plus Respiratory Bolt-On in the Birmingham Chronic Obstructive Pulmonary Disease Cohort Study.

OBJECTIVES: A respiratory bolt-on dimension for the EQ-5D-5L has recently been developed and valued by the general public. This study aimed to validate the EQ-5D-5L plus respiratory dimension (EQ-5D-5L+R) in a large group of patients with chronic obstructive pulmonary disease (COPD). METHODS: Validation was undertaken with data from the Birmingham COPD Cohort Study, a longitudinal UK study of COPD primary care patients. Data on the EQ-5D-5L+R were collected from 1008 responding participants during a follow-up questionnaire in 2017 and combined with (previously collected) data on patient and disease characteristics. Descriptive and correlation analyses were performed on the EQ-5D-5L+R dimensions and utilities, in relation to COPD characteristics and compared with the EQ-5D-5L without respiratory dimension. Multivariate regression models were estimated to test whether regression coefficients of clinical characteristics differed between the EQ-5D-5L+R utility and the EQ-5D-5L utility. RESULTS: Correlation coefficients for the EQ-5D-5L+R utility with COPD parameters were slightly higher than the EQ-5D-5L utility. Both instruments displayed discriminant validity but analyses in clinical subgroups of patients showed larger absolute differences in utilities for the EQ-5D-5L+R. In the multivariate analyses, only the coefficient for the COPD Assessment Test score was higher for the model using the EQ-5D-5L+R utility as outcome. CONCLUSIONS: This study showed that the addition of a respiratory domain to the EQ-5D-5L led to small improvements in the instrument's performance. Comparability of the EQ-5D across diseases, currently considered one of its strengths, would have to be traded off against a modest improvement in utility difference when adding the respiratory dimension.

Cost-effectiveness of the fixed-dose combination tiotropium/olodaterol versus tiotropium monotherapy or a fixed-dose combination of long-acting ß2-agonist/inhaled corticosteroid for COPD in Finland, Sweden and the Netherlands: a model-based study.

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) guidelines advocate treatment with combinations of long-acting bronchodilators for patients with COPD who have persistent symptoms or continue to have exacerbations while using a single bronchodilator. This study assessed the cost-utility of the fixed dose combination of the bronchodilators tiotropium and olodaterol versus two comparators, tiotropium monotherapy and long-acting ß2 agonist/inhaled corticosteroid (LABA/ICS) combinations, in three European countries: Finland, Sweden and the Netherlands. METHODS: A previously published COPD patient-level discrete event simulation model was updated with most recent evidence to estimate lifetime quality-adjusted life years (QALYs) and costs for COPD patients receiving either tiotropium/olodaterol, tiotropium monotherapy or LABA/ICS. Treatment efficacy covered impact on trough forced expiratory volume in 1 s (FEV1), total and severe exacerbations and pneumonias. The unit costs of medication, maintenance treatment, exacerbations and pneumonias were obtained for each country. The country-specific analyses adhered to the Finnish, Swedish and Dutch pharmacoeconomic guidelines, respectively. RESULTS: Treatment with tiotropium/olodaterol gained QALYs ranging from 0.09 (Finland and Sweden) to 0.11 (the Netherlands) versus tiotropium and 0.23 (Finland and Sweden) to 0.28 (the Netherlands) versus LABA/ICS. The Finnish payer's incremental cost-effectiveness ratio (ICER) of tiotropium/olodaterol was €11 000/QALY versus tiotropium and dominant versus LABA/ICS. The Swedish ICERs were €6200/QALY and dominant, respectively (societal perspective). The Dutch ICERs were €14 400 and €9200, respectively (societal perspective). The probability that tiotropium/olodaterol was cost-effective compared with tiotropium at the country-specific (unofficial) threshold values for the maximum willingness to pay for a QALY was 84% for Finland, 98% for Sweden and 99% for the Netherlands. Compared with LABA/ICS, this probability was 100% for all three countries. CONCLUSIONS: Based on the simulations, tiotropium/olodaterol is a cost-effective treatment option versus tiotropium or LABA/ICS in all three countries. In both Finland and Sweden, tiotropium/olodaterol is more effective and cost saving (ie, dominant) in comparison with LABA/ICS.

How to Address Uncertainty in Health Economic Discrete-Event Simulation Models: An Illustration for Chronic Obstructive Pulmonary Disease.

Background. Evaluation of personalized treatment options requires health economic models that include multiple patient characteristics. Patient-level discrete-event simulation (DES) models are deemed appropriate because of their ability to simulate a variety of characteristics and treatment pathways. However, DES models are scarce in the literature, and details about their methods are often missing. Methods. We describe 4 challenges associated with modeling heterogeneity and structural, stochastic, and parameter uncertainty that can be encountered during the development of DES models. We explain why these are important and how to correctly implement them. To illustrate the impact of the modeling choices discussed, we use (results of) a model for chronic obstructive pulmonary disease (COPD) as a case study. Results. The results from the case study showed that, under a correct implementation of the uncertainty in the model, a hypothetical intervention can be deemed as cost-effective. The consequences of incorrect modeling uncertainty included an increase in the incremental cost-effectiveness ratio ranging from 50% to almost a factor of 14, an extended life expectancy of approximately 1.4 years, and an enormously increased uncertainty around the model outcomes. Thus, modeling uncertainty incorrectly can have substantial implications for decision making. Conclusions. This article provides guidance on the implementation of uncertainty in DES models and improves the transparency of reporting uncertainty methods. The COPD case study illustrates the issues described in the article and helps understanding them better. The model R code shows how the uncertainty was implemented. For readers not familiar with R, the model's pseudo-code can be used to understand how the model works. By doing this, we can help other developers, who are likely to face similar challenges to those described here.

Cost-Effectiveness of Cancer Screening: Health and Costs in Life Years Gained.

INTRODUCTION: Studies reporting on the cost-effectiveness of cancer screening usually account for quality of life losses and healthcare costs owing to cancer but do not account for future costs and quality of life losses related to competing risks. This study aims to demonstrate the impact of medical costs and quality of life losses of other diseases in the life years gained on the cost-effectiveness of U.S. cancer screening. METHODS: Cost-effectiveness studies of breast, cervical, and colorectal cancer screening in the U.S. were identified using a systematic literature review. Incremental cost-effectiveness ratios of the eligible articles were updated by adding lifetime expenditures and health losses per quality-adjusted life year gained because of competing risks. This was accomplished using data on medical spending and quality of life by age and disease from the Medical Expenditure Panel Survey (2011-2015) combined with cause-deleted life tables. The study was conducted in 2018. RESULTS: The impact of quality of life losses and healthcare expenditures of competing risks in life years gained incurred owing to screening were the highest for breast cancer and the lowest for cervical cancer. The updates suggest that incremental cost-effectiveness ratios are underestimated by $10,300-$13,700 per quality-adjusted life year gained if quality of life losses and healthcare expenditures of competing risks are omitted in economic evaluations. Furthermore, cancer screening programs that were considered cost saving, were found not to be so following the inclusion of medical expenditures of competing risks. CONCLUSIONS: Practical difficulties in quantifying quality of life losses and healthcare expenditures owing to competing risks in life years gained can be overcome. Their inclusion can have a substantial impact on the cost-effectiveness of cancer screening programs.

Guidelines for multi-model comparisons of the impact of infectious disease interventions.

BACKGROUND: Despite the increasing popularity of multi-model comparison studies and their ability to inform policy recommendations, clear guidance on how to conduct multi-model comparisons is not available. Herein, we present guidelines to provide a structured approach to comparisons of multiple models of interventions against infectious diseases. The primary target audience for these guidelines are researchers carrying out model comparison studies and policy-makers using model comparison studies to inform policy decisions. METHODS: The consensus process used for the development of the guidelines included a systematic review of existing model comparison studies on effectiveness and cost-effectiveness of vaccination, a 2-day meeting and guideline development workshop during which mathematical modellers from different disease areas critically discussed and debated the guideline content and wording, and several rounds of comments on sequential versions of the guidelines by all authors. RESULTS: The guidelines provide principles for multi-model comparisons, with specific practice statements on what modellers should do for six domains. The guidelines provide explanation and elaboration of the principles and practice statements as well as some examples to illustrate these. The principles are (1) the policy and research question - the model comparison should address a relevant, clearly defined policy question; (2) model identification and selection - the identification and selection of models for inclusion in the model comparison should be transparent and minimise selection bias; (3) harmonisation - standardisation of input data and outputs should be determined by the research question and value of the effort needed for this step; (4) exploring variability - between- and within-model variability and uncertainty should be explored; (5) presenting and pooling results - results should be presented in an appropriate way to support decision-making; and (6) interpretation - results should be interpreted to inform the policy question. CONCLUSION: These guidelines should help researchers plan, conduct and report model comparisons of infectious diseases and related interventions in a systematic and structured manner for the purpose of supporting health policy decisions. Adherence to these guidelines will contribute to greater consistency and objectivity in the approach and methods used in multi-model comparisons, and as such improve the quality of modelled evidence for policy.

Exploring the Impact of Adding a Respiratory Dimension to the EQ-5D-5L.

Objectives. To evaluate the impact of adding a respiratory dimension (a bolt-on dimension) to the EQ-5D-5L health state valuations. Methods. Based on extensive regression and principal component analyses, 2 respiratory bolt-on candidates were formulated: R1, limitations in physical activities due to shortness of breath, and R2, breathing problems. Valuation interviews for the selected bolt-ons were performed with a representative sample from the Dutch general public using the standardized interview protocol and software of the EuroQol group. Hybrid models based on the combined time-tradeoff (TTO) and discrete choice experiment (DCE) data were estimated to assess whether the 5 levels of the respiratory bolt-on led to significant changes in utility values. Results. For each bolt-on candidate, slightly more than 200 valuation interviews were conducted. Mean TTO values and DCE choice probabilities for health states with a level 4 or 5 for the respiratory dimension were significantly lower compared with the same health states in the Dutch EQ-5D-5L valuation study without the respiratory dimension. Results of hybrid models showed that for the bolt-on "limitations in physical activities," the utility decrements were significant for level 3 (-0.055), level 4 (-0.087), and level 5 (-0.135). For "breathing problems," the utility decrements for the same levels were greater (-0.086, -0.219, and -0.327, respectively). Conclusions. The addition of each of the 2 respiratory bolt-ons to the EQ-5D-5L had a significant effect on the valuation of health states with severe levels for the bolt-on. The bolt-on dimension "breathing problems" showed the greatest utility decrements and therefore seems the most appropriate respiratory bolt-on dimension.

Long-term cost-effectiveness of the fixed-dose combination of tiotropium plus olodaterol based on the DYNAGITO trial results.

PURPOSE: Combinations of long-acting bronchodilators are recommended to reduce the rate of COPD exacerbations. Evidence from the DYNAGITO trial showed that the fixed-dose combination of tiotropium + olodaterol reduced the annual rate of total exacerbations (P<0.05) compared with tiotropium monotherapy. This study aimed to estimate the cost-effectiveness of the fixed-dose combination of tiotropium + olodaterol vs tiotropium monotherapy in COPD patients in the French setting. PATIENTS AND METHODS: A recently developed COPD patient-level simulation model was used to simulate the lifetime effects and costs for 15,000 patients receiving either tiotropium + olodaterol or tiotropium monotherapy by applying the reduction in annual exacerbation rate as observed in the DYNAGITO trial. The model was adapted to the French setting by including French unit costs for treatment medication, COPD maintenance treatment, COPD exacerbations (moderate or severe), and pneumonia. The main outcomes were the annual (severe) exacerbation rate, the number of quality-adjusted life-years (QALYs), and total lifetime costs. RESULTS: The number of QALYs for treatment with tiotropium + olodaterol was 0.042 higher compared with tiotropium monotherapy. Using a societal perspective, tiotropium + olodaterol resulted in a cost increase of +€123 and an incremental cost-effectiveness ratio (ICER) of €2,900 per QALY compared with tiotropium monotherapy. From a French National Sickness Fund perspective, total lifetime costs were reduced by €272 with tiotropium + olodaterol, resulting in tiotropium + olodaterol being the dominant treatment option, that is, more effects with less costs. Sensitivity analyses showed that reducing the cost of exacerbations by 34% increased the ICER to €15,400, which could still be considered cost-effective in the French setting. CONCLUSION: Treatment with tiotropium + olodaterol resulted in a gain in QALYs and savings in costs compared with tiotropium monotherapy using a National Sickness Fund perspective in France. From the societal perspective, tiotropium + olodaterol was found to be cost-effective with a low cost per QALY.

Broadening the Perspective of Cost-Effectiveness Modeling in Chronic Obstructive Pulmonary Disease: A New Patient-Level Simulation Model Suitable to Evaluate Stratified Medicine.

OBJECTIVES: To develop a health economic model that included a great diversity of patient characteristics and outcomes for chronic obstructive pulmonary disease (COPD), which can be used to inform decisions about stratified medicine in COPD. METHODS: The choice of patient characteristics and outcomes to include in the model was based on 3 literature reviews on multidimensional prognostic COPD indices, COPD phenotypes, and treatment effects in subgroups. A conceptual model was constructed including 14 patient characteristics, 7 intermediate outcomes (lung function, physical activity, exercise capacity, symptoms, disease-specific quality of life, exacerbations, and pneumonias), and 3 final outcomes (mortality, quality-adjusted life-years [QALYs], and costs). Regression equations describing the statistical associations between the patient characteristics and intermediate and final outcomes were estimated using the longitudinal data of 5 large COPD trials (19,378 patients). A patient-level simulation model was developed in which individual patients from the baseline population of the 5 trials are sampled and their outcomes over lifetime are predicted based on the regression equations. RESULTS: The base-case analysis (single-arm simulation representing treatment with tiotropium) showed that patients had a mean lung function decline of 43 mL/year, 0.62 exacerbations/year, a worsening of their physical activity and quality of life with 1.48 and 1.10 points/year, a life expectancy of 11.2 years, 7.25 QALYs, and total lifetime costs of £24,891. Results for a selection of treatment scenarios and subgroups were shown to demonstrate the potential of the model. CONCLUSIONS: We developed a unique patient-level simulation model that can be used to evaluate COPD treatment options for a variety of subgroups.

Prediction models for exacerbations in different COPD patient populations: comparing results of five large data sources.

BACKGROUND AND OBJECTIVES: Exacerbations are important outcomes in COPD both from a clinical and an economic perspective. Most studies investigating predictors of exacerbations were performed in COPD patients participating in pharmacological clinical trials who usually have moderate to severe airflow obstruction. This study was aimed to investigate whether predictors of COPD exacerbations depend on the COPD population studied. METHODS: A network of COPD health economic modelers used data from five COPD data sources - two population-based studies (COPDGene® and The Obstructive Lung Disease in Norrbotten), one primary care study (RECODE), and two studies in secondary care (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoint and UPLIFT) - to estimate and validate several prediction models for total and severe exacerbations (= hospitalization). The models differed in terms of predictors (depending on availability) and type of model. RESULTS: FEV1% predicted and previous exacerbations were significant predictors of total exacerbations in all five data sources. Disease-specific quality of life and gender were predictors in four out of four and three out of five data sources, respectively. Age was significant only in the two studies including secondary care patients. Other significant predictors of total exacerbations available in one database were: presence of cough and wheeze, pack-years, 6-min walking distance, inhaled corticosteroid use, and oxygen saturation. Predictors of severe exacerbations were in general the same as for total exacerbations, but in addition low body mass index, cardiovascular disease, and emphysema were significant predictors of hospitalization for an exacerbation in secondary care patients. CONCLUSIONS: FEV1% predicted, previous exacerbations, and disease-specific quality of life were predictors of exacerbations in patients regardless of their COPD severity, while age, low body mass index, cardiovascular disease, and emphysema seem to be predictors in secondary care patients only.

External Validation of Health Economic Decision Models for Chronic Obstructive Pulmonary Disease (COPD): Report of the Third COPD Modeling Meeting.

OBJECTIVES: To validate outcomes of presently available chronic obstructive pulmonary disease (COPD) cost-effectiveness models against results of two large COPD trials-the 3-year TOwards a Revolution in COPD Health (TORCH) trial and the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial. METHODS: Participating COPD modeling groups simulated the outcomes for the placebo-treated groups of the TORCH and UPLIFT trials using baseline characteristics of the trial populations as input. Groups then simulated treatment effectiveness by using relative reductions in annual decline in lung function and exacerbation frequency observed in the most intensively treated group compared with placebo as input for the models. Main outcomes were (change in) total/severe exacerbations and mortality. Furthermore, the absolute differences in total exacerbations and quality-adjusted life-years (QALYs) were used to approximate the cost per exacerbation avoided and the cost per QALY gained. RESULT: Of the six participating models, three models reported higher total exacerbation rates than observed in the TORCH trial (1.13/patient-year) (models: 1.22-1.48). Four models reported higher rates than observed in the UPLIFT trial (0.85/patient-year) (models: 1.13-1.52). Two models reported higher mortality rates than in the TORCH trial (15.2%) (models: 20.0% and 30.6%) and the UPLIFT trial (16.3%) (models: 24.8% and 36.0%), whereas one model reported lower rates (9.8% and 12.1%, respectively). Simulation of treatment effectiveness showed that the absolute reduction in total exacerbations, the gain in QALYs, and the cost-effectiveness ratios did not differ from the trials, except for one model. CONCLUSIONS: Although most of the participating COPD cost-effectiveness models reported higher total exacerbation rates than observed in the trials, estimates of the absolute treatment effect and cost-effectiveness ratios do not seem different from the trials in most models.

Patient Heterogeneity in Health Economic Decision Models for Chronic Obstructive Pulmonary Disease: Are Current Models Suitable to Evaluate Personalized Medicine?

OBJECTIVES: To assess how suitable current chronic obstructive pulmonary disease (COPD) cost-effectiveness models are to evaluate personalized treatment options for COPD by exploring the type of heterogeneity included in current models and by validating outcomes for subgroups of patients. METHODS: A consortium of COPD modeling groups completed three tasks. First, they reported all patient characteristics included in the model and provided the level of detail in which the input parameters were specified. Second, groups simulated disease progression, mortality, quality-adjusted life-years (QALYs), and costs for hypothetical subgroups of patients that differed in terms of sex, age, smoking status, and lung function (forced expiratory volume in 1 second [FEV1] % predicted). Finally, model outcomes for exacerbations and mortality for subgroups of patients were validated against published subgroup results of two large COPD trials. RESULTS: Nine COPD modeling groups participated. Most models included sex (seven), age (nine), smoking status (six), and FEV1% predicted (nine), mainly to specify disease progression and mortality. Trial results showed higher exacerbation rates for women (found in one model), higher mortality rates for men (two models), lower mortality for younger patients (four models), and higher exacerbation and mortality rates in patients with severe COPD (four models). CONCLUSIONS: Most currently available COPD cost-effectiveness models are able to evaluate the cost-effectiveness of personalized treatment on the basis of sex, age, smoking, and FEV1% predicted. Treatment in COPD is, however, more likely to be personalized on the basis of clinical parameters. Two models include several clinical patient characteristics and are therefore most suitable to evaluate personalized treatment, although some important clinical parameters are still missing.

Projecting the COPD population and costs in England and Scotland: 2011 to 2030.

We aimed to estimate the prevalence, healthcare costs and number of deaths among people with chronic obstructive pulmonary disease (COPD) in England and Scotland 2011-2030. We adapted the Dutch COPD Model by using English and Scottish demographic, COPD incidence, COPD prevalence, smoking prevalence and mortality data to make projections. In England, the prevalence of COPD was estimated to be 1.79% (95% uncertainty interval 1.77-1.81) in 2011, increasing to 2.19% (1.85-2.33) by 2030. In Scotland, prevalence was 2.03% (1.96-2.10) in 2011 increasing to 2.20% (1.98-2.40) in 2030. These increases were driven by more women developing COPD. Annual direct healthcare costs of COPD in England were estimated to increase from £1.50 billon (1.18-2.50) in 2011 to £2.32 (1.85-3.08) billion in 2030. In Scotland, costs increased from £159 million (128-268) in 2011 to £207 (165-274) million in 2030. The deaths in England were estimated to increase from 99,200 (92,500-128,500) in 2011, to 129,400 (126,400-133,400) by 2030. In Scotland, in 2011 there were 9,700 (9,000-12,300) deaths and 13,900 (13,400-14,500) deaths in 2030. The number of people with COPD will increase substantially over the coming years in England and Scotland, particularly in females. Services need to adapt to this increasing demand.

Preventing dementia by promoting physical activity and the long-term impact on health and social care expenditures.

BACKGROUND: Preventing dementia has been proposed to increase population health as well as reduce the demand for health and social care. Our aim was to evaluate whether preventing dementia by promoting physical activity (PA) a) improves population health or b) reduces expenditure for both health and social care if one takes into account the additional demand in health and social care caused by increased life expectancy. METHODS: A simulation model was developed that models the relation between PA, dementia, mortality, and the use of health care and social care in England. With this model, scenarios were evaluated in which different assumptions were made about the increase in PA level in (part of) the population. RESULTS: Lifetime spending on health and social care related to dementia was highest for the physically inactive (£28,100/£28,900 for 40-year-old males/females), but spending on other diseases was highest for those that meet PA recommendations (£55,200/£43,300 for 40-year-old males/females) due to their longer life expectancies. If the English population aged 40-65 were to increase their PA by one level, life expectancy would increase by 0.23years and health and social care expenditures would decrease by £400 per person. CONCLUSIONS: Preventing dementia by increasing PA increases life expectancy and can result in decreased spending overall on health and social care, even after additional spending during life years gained has been taken into account. If prevention is targeted at the physically inactive, savings in dementia-related costs outweigh the additional spending in life years gained.

Cost-effectiveness models for chronic obstructive pulmonary disease: cross-model comparison of hypothetical treatment scenarios.

OBJECTIVES: To compare different chronic obstructive pulmonary disease (COPD) cost-effectiveness models with respect to structure and input parameters and to cross-validate the models by running the same hypothetical treatment scenarios. METHODS: COPD modeling groups simulated four hypothetical interventions with their model and compared the results with a reference scenario of no intervention. The four interventions modeled assumed 1) 20% reduction in decline in lung function, 2) 25% reduction in exacerbation frequency, 3) 10% reduction in all-cause mortality, and 4) all these effects combined. The interventions were simulated for a 5-year and lifetime horizon with standardization, if possible, for sex, age, COPD severity, smoking status, exacerbation frequencies, mortality due to other causes, utilities, costs, and discount rates. Furthermore, uncertainty around the outcomes of intervention four was compared. RESULTS: Seven out of nine contacted COPD modeling groups agreed to participate. The 5-year incremental cost-effectiveness ratios (ICERs) for the most comprehensive intervention, intervention four, was €17,000/quality-adjusted life-year (QALY) for two models, €25,000 to €28,000/QALY for three models, and €47,000/QALY for the remaining two models. Differences in the ICERs could mainly be explained by differences in input values for disease progression, exacerbation-related mortality, and all-cause mortality, with high input values resulting in low ICERs and vice versa. Lifetime results were mainly affected by the input values for mortality. The probability of intervention four to be cost-effective at a willingness-to-pay value of €50,000/QALY was 90% to 100% for five models and about 70% and 50% for the other two models, respectively. CONCLUSIONS: Mortality was the most important factor determining the differences in cost-effectiveness outcomes between models.

Ivacaftor for the treatment of patients with cystic fibrosis and the G551D mutation: a systematic review and cost-effectiveness analysis.

BACKGROUND: Ivacaftor (Kalydeco(®), Vertex Pharmaceuticals) is the first of a new class of drugs that target the underlying protein defect in cystic fibrosis (CF). It is aimed at patients with the G551D (glycine to aspartate change in nucleotide 1784 in exon 11) mutation; 5.7% of patients with CF in the UK have this mutation. OBJECTIVES: To review the clinical effectiveness and cost-effectiveness of ivacaftor for the treatment of CF in patients aged ≥ 6 years who have the G551D mutation. METHODS: Ten databases, including MEDLINE and EMBASE, were searched from inception to July 2012. Studies that evaluated ivacaftor for the treatment of adults and children (≥ 6 years) with at least one G551D mutation were eligible. There were insufficient data to conduct a formal meta-analysis. The manufacturer of ivacaftor, Vertex Pharmaceuticals, submitted a deterministic patient-level simulation model for the assessment of the lifetime cost-effectiveness of ivacaftor. We modified the model where values were not UK-specific or not recent, or where better estimates could be found. The only change to the model structure was the addition of lung transplantations. We changed utility values, annual decline in percentage predicted forced expiratory volume in 1 second (FEV1), and the baseline exacerbation rate, and used data from the CF Registry to estimate the relation between costs, age and percentage predicted FEV1. Estimates of treatment effect of ivacaftor came from the clinical effectiveness review. We modelled three scenarios for the longer-term effects of ivacaftor. We also modelled an 'optimistic' scenario for patients aged < 12 years with little lung damage. We conducted a budget impact analysis to estimate the total cost to the NHS of introducing ivacaftor in England. RESULTS: Three studies were included: a randomised controlled trial (RCT) in adults (n = 167) (≥ 12 years), a RCT in children (n = 26) (6-11 years), and an open-label extension study of the two RCTs. Both RCTs reported significantly greater changes from baseline in all measures of lung function in patients receiving ivacaftor than in those receiving placebo. The mean difference in change in percentage predicted FEV1 was 10.5 [95% confidence interval (CI) 8.5 to 12.5] percentage points in the adults' study and 10.0 (95% CI 4.5 to 15.5) percentage points in the children's study at 48 weeks. Improvements in lung function were seen across all subgroups investigated (age, sex, study region and lung function). There were significantly greater improvements in the ivacaftor group than in the placebo group for all outcomes assessed (exacerbations, quality of life, sweat chloride and weight) with the exception of quality of life in children. Improvements were maintained in the open-label trial. Adverse events were mainly minor and comparable across treatment groups. Both RCTs reported more withdrawals in the placebo group than in the ivacaftor group. The incremental cost-effectiveness ratio varied between £335,000 and £1,274,000 per quality-adjusted life-year gained. The total additional lifetime costs for all eligible CF patients in England ranged from £438M to £479M; the lifetime cost for standard care only was £72M. CONCLUSIONS: The available evidence suggests that ivacaftor is a clinically effective treatment for patients with CF and the G551D mutation; the high cost of ivacaftor may prove an obstacle in the uptake of this treatment. The main priority for further research is the long-term effectiveness of ivacaftor. STUDY REGISTRATION: This study is registered as PROSPERO CRD42012002516. SOURCE OF FUNDING: The National Institute for Health Research Health Technology Assessment programme.

[Societal costs of asthma, COPD and respiratory allergy]. / Maatschappelijke kosten van astma, COPD en respiratoire allergie.

OBJECTIVE: To estimate the societal costs of asthma, COPD and respiratory allergy for the year 2007 and future healthcare costs for the period 2007-2032. DESIGN: Descriptive study. METHODS: Representative registries were used to estimate the healthcare costs of asthma, COPD and respiratory allergy for the year 2007. A simulation model for asthma and COPD and a demographic projection for respiratory allergy were used to determine future healthcare costs. Production losses due to sick leave and work incapacity were calculated using the friction-cost method. RESULTS: Total healthcare costs for asthma, COPD and respiratory allergy in 2007 were estimated at 287, 415 and 103 million euros respectively; on average 530, 1400 and 170 euros per patient with asthma, COPD and respiratory allergy. Average costs of sick leave for asthma were on average 1200 euros and for COPD 1900 euros per employee per year. The costs of work incapacity of an employee with COPD were 1200 euros. There is expected to be an increase in the number of patients from 443,000 in 2007 to 567,000 in 2032 for asthma and from 335,000 to 600,000 for COPD. The number of patients with a respiratory allergy are expected to remain approximately stable at 625,000 patients. The healthcare costs for respiratory allergy are expected to rise by 73%, those for asthma to double, and those for COPD to triple. CONCLUSION: Patients with asthma and COPD have high healthcare costs. Sick leave makes up a large part of the costs of asthma and COPD. In addition, the costs of work incapacity for employees with COPD are high. The number of patients with asthma and COPD will rise in the coming decades, as well as the healthcare costs for these diseases.

An official American Thoracic Society/European Respiratory Society statement: key concepts and advances in pulmonary rehabilitation.

BACKGROUND: Pulmonary rehabilitation is recognized as a core component of the management of individuals with chronic respiratory disease. Since the 2006 American Thoracic Society (ATS)/European Respiratory Society (ERS) Statement on Pulmonary Rehabilitation, there has been considerable growth in our knowledge of its efficacy and scope. PURPOSE: The purpose of this Statement is to update the 2006 document, including a new definition of pulmonary rehabilitation and highlighting key concepts and major advances in the field. METHODS: A multidisciplinary committee of experts representing the ATS Pulmonary Rehabilitation Assembly and the ERS Scientific Group 01.02, "Rehabilitation and Chronic Care," determined the overall scope of this update through group consensus. Focused literature reviews in key topic areas were conducted by committee members with relevant clinical and scientific expertise. The final content of this Statement was agreed on by all members. RESULTS: An updated definition of pulmonary rehabilitation is proposed. New data are presented on the science and application of pulmonary rehabilitation, including its effectiveness in acutely ill individuals with chronic obstructive pulmonary disease, and in individuals with other chronic respiratory diseases. The important role of pulmonary rehabilitation in chronic disease management is highlighted. In addition, the role of health behavior change in optimizing and maintaining benefits is discussed. CONCLUSIONS: The considerable growth in the science and application of pulmonary rehabilitation since 2006 adds further support for its efficacy in a wide range of individuals with chronic respiratory disease.

Cost-effectiveness of tiotropium versus salmeterol: the POET-COPD trial.

The aim of this study was to perform a 1-yr trial-based cost-effectiveness analysis (CEA) of tiotropium versus salmeterol followed by a 5-yr model-based CEA. The within-trial CEA, including 7,250 patients with moderate to very severe chronic obstructive pulmonary disease (COPD), was performed alongside the 1-yr international randomised controlled Prevention of Exacerbations with Tiotropium (POET)-COPD trial comparing tiotropium with salmeterol regarding the effect on exacerbations. Main end-points of the trial-based analysis were costs, number of exacerbations and exacerbation days. The model-based analysis was conducted to extrapolate results to 5 yrs and to calculate quality-adjusted life years (QALYs). 1-yr costs per patient from the German statutory health insurance (SHI) perspective and the societal perspective were €126 (95% uncertainty interval (UI) €55-195) and €170 (95% UI €77-260) higher for tiotropium, respectively. The annual number of exacerbations was 0.064 (95% UI 0.010-0.118) lower for tiotropium, leading to a reduction in exacerbation-related costs of €87 (95% UI €19-157). The incremental cost-effectiveness ratio was €1,961 per exacerbation avoided from the SHI perspective and €2,647 from the societal perspective. In the model-based analyses, the 5-yr costs per QALY were €3,488 from the SHI perspective and €8,141 from the societal perspective. Tiotropium reduced exacerbations and exacerbation-related costs, but increased total costs. Tiotropium can be considered cost-effective as the resulting cost-effectiveness ratios were below commonly accepted willingness-to-pay thresholds.

Developing and applying a stochastic dynamic population model for chronic obstructive pulmonary disease.

OBJECTIVES: To develop a stochastic population model of disease progression in chronic obstructive pulmonary disease (COPD) that includes the effects of COPD exacerbations on health-related quality of life, costs, disease progression, and mortality and can be used to assess the effects of a wide range of interventions. METHODS: The model is a multistate Markov model with time varying transition rates specified by age, sex, smoking status, COPD disease severity, and/or exacerbation type. The model simulates annual changes in COPD prevalence due to COPD incidence, exacerbations, disease progression (annual decline in the forced expiratory volume in 1 second as percentage of the predicted value), and mortality. The main outcome variables are quality-adjusted life years, total exacerbations, and COPD-related health care costs. Exacerbation-related input parameters were based on quantitative meta-analysis. All important model parameters are entered into the model as probability distributions. To illustrate the potential use of the model, costs and effects were calculated for 3-year implementation of three different COPD interventions, one pharmacologic, one on smoking cessation, and one on pulmonary rehabilitation using a time horizon of 10 years for reporting outcomes. RESULTS: Compared with minimal treatment the cost/quality-adjusted life year was €8,300 for the pharmacologic intervention, €10,800 for the smoking cessation therapy, €8,700 for the combination of the pharmacologic intervention and the smoking cessation therapy, and €17,200 for the pulmonary rehabilitation program. The probability of the interventions to be cost-effective at a ceiling ratio of €20,000 varied from 58% to 100%. CONCLUSIONS: The COPD model provides policy makers with information about the long-term costs and effects of interventions over the entire chain of care, from primary prevention to care for very severe COPD and includes uncertainty around the outcomes.