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Maureen PMH Rutten-van Mölken,1 Elisabeth Sophia Hartgers-Gubbels,2 Michael Chambers3 1Erasmus School of Health Policy & Management, Erasmus University Rotterdam, Rotterdam, the Netherlands; 2Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 3MC Healthcare Evaluation, London, UKCorrespondence: Elisabeth Sophia Hartgers-Gubbels, Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany, Email lisa.hartgers-gubbels@boehringer-ingelheim.comAbstract: How is a cost-effectiveness analysis constructed and used? In this episode of the Value Insider podcast, host Mike Chambers speaks with Prof. Maureen Rutten-van Mölken about economic evaluations in healthcare and how value is considered in these evaluations. Prof. Rutten-van Mölken is professor of Economic Evaluation of Innovations for Health at the Erasmus University Rotterdam in the Netherlands. She leads the Erasmus HTA department and is Scientific Director of the Institute for Medical Technology Assessment (iMTA). Prof Rutten-van Mölken explains how comparative assessments can help us understand which treatments offer the best value-for-money as reimbursement can only be allocated to a selection of all possible treatments.Keywords: market access, healthcare reimbursement, health technology assessment, HTA, value demonstration, health economics and outcomes research, payer

Martine Hoogendoorn,1 Isaac Corro Ramos,1 Michael Baldwin,2 Laura Luciani,3 Cecile Fabron,4 Bruno Detournay,4 Maureen PMH Rutten-van Mölken1,5 1institute for Medical Technology Assessment (iMTA), Erasmus University Rotterdam, Rotterdam, the Netherlands; 2Boehringer Ingelheim GmbH, Ingelheim, Germany; 3Boehringer Ingelheim France, Paris, France; 4Cemka-Eval, Bourg-la-Reine, France; 5Erasmus School of Health Policy & Management (ESHPM), Erasmus University Rotterdam, Rotterdam, the Netherlands 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

Lucas MA Goossens1, Christine L Baker2, Brigitta U Monz3, Kelly H Zou2, Maureen PMH Rutten-van Mölken11Institute for Medical Technology Assessment, Erasmus University, Rotterdam, The Netherlands; 2Pfizer Inc, New York City, NY, USA; 3Boehringer Ingelheim International GmbH, Ingelheim am Rhein, GermanyPurpose: When comparing chronic obstructive lung disease (COPD) interventions in database research, it is important to adjust for severity. Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines grade severity according to lung function. Most databases lack data on lung function. Previous database research has approximated COPD severity using demographics and healthcare utilization. This study aims to derive an algorithm for COPD severity using baseline data from a large respiratory trial (UPLIFT).Methods: Partial proportional odds logit models were developed for probabilities of being in GOLD stages II, III and IV. Concordance between predicted and observed stage was assessed using kappa-statistics. Models were estimated in a random selection of 2/3 of patients and validated in the remainder. The analysis was repeated in a subsample with a balanced distribution across severity stages. Univariate associations of COPD severity with the covariates were tested as well.Results: More severe COPD was associated with being male and younger, having quit smoking, lower BMI, osteoporosis, hospitalizations, using certain medications, and oxygen. After adjusting for these variables, co-morbidities, previous healthcare resource use (eg, emergency room, hospitalizations) and inhaled corticosteroids, xanthines, or mucolytics were no longer independently associated with COPD severity, although they were in univariate tests. The concordance was poor (kappa = 0.151) and only slightly better in the balanced sample (kappa = 0.215).Conclusion: COPD severity cannot be reliably predicted from demographics and healthcare use. This limitation should be considered when interpreting findings from database studies, and additional research should explore other methods to account for COPD severity.Keywords: GOLD, healthcare resource use, partial proportional odds logit

Aims: Remote haemodynamic monitoring with an implantable pulmonary artery (PA) sensor has been shown to reduce heart failure (HF) hospitalizations and improve quality of life. Cost-effectiveness analyses studying the value of remote haemodynamic monitoring in a European healthcare system with a contemporary standard care group are lacking., Methods and Results: A Markov model was developed to estimate the cost-effectiveness of PA-guided therapy compared to the standard of care based upon patient-level data of the MONITOR-HF trial performed in the Netherlands in patients with chronic HF (New York Heart Association class III and at least one previous HF hospitalization). Cost-effectiveness was measured as the incremental cost per quality-adjusted life year (QALY) gained from the Dutch societal perspective with a lifetime horizon which encompasses a wide variety of costs including costs of hospitalizations, monitoring time, telephone contacts, laboratory assessments, and drug changes in both treatment groups. In the base-case analysis, PA-guided therapy increased costs compared to standard of care by €12 121. The QALYs per patient for PA-guided therapy and standard of care was 4.07 and 3.481, respectively, reflecting a gain of 0.58 QALYs. The resulting incremental cost-effectiveness ratio was €20 753 per QALY, which is below the Dutch willingness-to-pay threshold of €50 000 per QALY gained for HF., Conclusions: The current cost-effectiveness study suggests that remote haemodynamic monitoring with PA-guided therapy on top of standard care is likely to be cost-effective for patients with symptomatic moderate-to-severe HF in the Netherlands., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objective: To evaluate the implementation of a guideline-based, integrated, standardised, personal approach in patients with Chronic Obstructive Pulmonary Disease (COPD) or Asthma in a real-life situation., Methods: Patients at the outpatient clinic of the department of pulmonary disease were included in a controlled cohort study, comparing the use of diagnostic items and 'Personalised care plans' (PCPs) in patients with obstructive lung disease before (2013) and after (2015) implementation of a personalised diagnostic pathway. Results were compared with reference data (2016) from two control hospitals that used the same guidelines but did not implement this pathway., Results: 100 patients were selected for all three cohorts. After implementing the diagnostic pathway in 2015, 35 % of patients visited attended all pre-planned appointments, whereas 65 % of patients did not: they were diagnosed using usual care. Factors contributing to patients not attending the diagnostic care pathway were: the logistical complexity and intensity of the 2-day pathway, patients willingness to participate in a personalised pathway, and low social economic status or low literacy. After the implementation of the pathway, a significant improvement was seen in the number of PCPs (P < 0.001) and the number of diagnostic items registered recorded in the patients' electronic medical records (P < 0.001)., Conclusion: Implementing a standardised diagnostic pathway in a real-life population significantly improved the number of personalised care plans, demonstrating that the implementation of holistic care planning is feasible in this population. Nevertheless, the pathway needs further improvements to maximize the number of patients benefitting from it, including logistical streamlining, removing unnecessary diagnostic tools, and increasing the focus on low literacy. Additionally, we found that implementing existing guidelines in a real life context is complex. Therefore, it is required to prioritize the translation of current guidelines into every-day practice, before expanding existing guidelines and protocols., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

To stimulate the integration of chronic care across disciplines, the Netherlands has implemented single-disease management programmes (SDMPs) in primary care since 2010; for example, for COPD, type 2 diabetes mellitus, and cardiovascular diseases. These disease-specific chronic care programmes are funded by bundled payments. For chronically ill patients with multimorbidity or with problems in other domains of health, this approach was shown to be less fit for purpose. As a result, we are currently witnessing several initiatives to broaden the scope of these programmes, aiming to provide truly person-centred integrated care (PC-IC). This raises the question if it is possible to design a payment model that would support this transition. We present an alternative payment model that combines a person-centred bundled payment with a shared savings model and pay-for-performance elements. Based on theoretical reasoning and results of previous evaluation studies, we expect the proposed payment model to stimulate integration of person-centred care between primary healthcare providers, secondary healthcare providers, and the social care domain. We also expect it to incentivise cost-conscious provider-behaviour, while safeguarding the quality of care, provided that adequate risk-mitigating actions, such as case-mix adjustment and cost-capping, are taken.

Introduction: New glucose-monitoring technologies have different cost-benefit profiles compared with traditional finger-prick tests, resulting in a preference-sensitive situation for patients. This study aimed to assess the relative value adults with diabetes assign to device attributes in two countries., Research Design and Methods: Adults with type 1 or 2 diabetes from the Netherlands (n=226) and Poland (n=261) completed an online discrete choice experiment. Respondents choose between hypothetical glucose monitors described using seven attributes: precision, effort to check, number of finger pricks required, risk of skin irritation, information provided, alarm function and out-of-pocket costs. Panel mixed logit models were used to determine attribute relative importance and to calculate expected uptake rates and willingness to pay (WTP)., Results: The most important attribute for both countries was monthly out-of-pocket costs. Polish respondents were more likely than Dutch respondents to choose a glucose-monitoring device over a standard finger prick and had higher WTP for a device. Dutch respondents had higher WTP for device improvements in an effort to check and reduce the number of finger pricks a device requires., Conclusion: Costs are the primary concern of patients in both countries when choosing a glucose monitor and would likely hamper real-world uptake. The costs-benefit profiles of such devices should be critically reviewed., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

OnkoNetwork is a patient navigation program established in the Moritz Kaposi General Hospital to improve the timeliness and completeness of cancer investigations and treatment. The H2020 SELFIE consortium selected OnkoNetwork as a promising integrated care initiative in Hungary and conducted a multicriteria decision analysis based on health, patient experience, and cost outcomes. In this paper, a more detailed analysis of clinical impacts is provided in the largest subgroup, non-small cell lung cancer (NSCLC) patients. A retrospective cohort study was conducted, enrolling new cancer suspect patients with subsequently confirmed NSCLC in two annual periods, before and after OnkoNetwork implementation (control and intervention cohorts, respectively). To control for selection bias and confounding, baseline balance was improved via propensity score weighting. Overall survival was analyzed in univariate and multivariate weighted Cox regression models and the effect was further characterized in a counterfactual analysis. Our analysis included 123 intervention and 173 control NSCLC patients from early to advanced stage, with significant between-cohort baseline differences. The propensity score-based weighting resulted in good baseline balance. A large survival benefit was observed in the intervention cohort, and intervention was an independent predictor of longer survival in a multivariate analysis when all baseline characteristics were included (HR = 0.63, p = 0.039). When post-baseline variables were included in the model, belonging to the intervention cohort was not an independent predictor of survival, but the survival benefit was explained by slightly better stage distribution and ECOG status at treatment initiation, together with trends for broader use of PET-CT and higher resectability rate. In conclusion, patient navigation is a valuable tool to improve cancer outcomes by facilitating more timely and complete cancer diagnostics. Contradictory evidence in the literature may be explained by common sources of bias, including the wait-time paradox and adjustment to intermediate outcomes., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: the described research was conducted as part of the H2020 SELFIE project that has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 634288. JGP, MCs, MRM, KI, ZK, and ZV are employees of SELFIE beneficiaries. The employer of JGP, MCs, ZK, and ZV received additional EU research grants related to the evaluation of smoking cessation interventions and national cancer screening programs. MM, ÉSE, GL, and ASz are employees of Móritz Kaposi General Hospital, this Hospital initiated the OnkoNetwork program and received study funding from the SELFIE grant. These interests do not alter our adherence to PLOS ONE policies on sharing data and materials. (as detailed online in the guide for authors http://journals.plos.org/plosone/s/competing-interests).

Introduction: Policies to adequately respond to the rise in multimorbidity have top-priority. To understand the actual burden of multimorbidity, this study aimed to: 1) estimate the trend in prevalence of multimorbidity in the Netherlands, 2) study the association between multimorbidity and physical and mental health outcomes and healthcare cost, and 3) investigate how the association between multimorbidity and health outcomes interacts with socio-economic status (SES)., Methods: Prevalence estimates were obtained from a nationally representative pharmacy database over 2007-2016. Impact on costs was estimated in a fixed effect regression model on claims data over 2009-2015. Data on physical and mental health and SES were obtained from the National Health Survey in 2017, in which the Katz-10 was used to measure limitations in activities of daily living (ADL) and the Mental Health Inventory (MHI) to measure mental health. SES was approximated by the level of education. Generalized linear models (2-part models for ADL) were used to analyze the health data. In all models an indicator variable for the presence or absence of multimorbidity was included or a categorical variable for the number of chronic conditions. Interactions terms of multimorbidity and educational level were added into the previously mentioned models., Results: Over the past ten years, there was an increase of 1.6%-point in the percentage of people with multimorbidity. The percentage of people with three or more conditions increased with +2.1%-point. People with multimorbidity had considerably worse physical and mental health outcomes than people without multimorbidity. For the ADL, the impact of multimorbidity was three times greater in the lowest educational level than in the highest educational level. For the MHI, the impact of multimorbidity was two times greater in the lowest than in the highest educational level. Each additional chronic condition was associated with a greater worsening in health outcomes. Similarly, for costs, where there was no evidence of a diminishing impact of additional conditions either. In patients with multimorbidity total healthcare costs were on average €874 higher than in patients with a single morbidity., Conclusion: The impact of multimorbidity on health and costs seems to be greater in the sicker and lower educated population., Competing Interests: The authors have declared that no competing interests exist.

Background: The concept of hospital-at-home means that home treatment is provided to patients who would otherwise have been treated in the hospital. This may lead to lower costs, but estimates of savings may be overstated if inpatient hospital costs are priced incorrectly., Objective: The objective of this study was to evaluate the quality of cost analyses of hospital-at-home studies for acute conditions published from 1996 through 2019 and to present an overview of evidence., Design: Literature review DATA SOURCES: The PubMed and NHS EED databases were searched., Review Methods: The overall quality of studies was evaluated based on Quality of Health Economic Studies (QHES) score, design, sample size, alignment of cost calculation with study perspective, time horizon, use of tariffs or real resource use and clarity of calculations. Furthermore, we systematically assessed whether cost savings were likely to be overestimated, based on criteria about the costing of inpatient hospital days, informal care costs and bias., Results: We identified 48 studies. The average QHES score was 60 out of a maximum of 100 points. Almost all studies violated one or more criteria for the risk of overestimation of cost savings. The most frequent problems were the use of average unit prices per inpatient day (not taking into account the decreasing intensity of care) and biased designs. Most studies found cost differences in favour of hospital-at-home; the range varied from savings of €8773 to a cost increase of €2316 per patient., Conclusion: Overall quality of studies was not good, with some exceptions. Many cost savings were probably overestimated., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest. The study was not externally funded., (Copyright © 2020. Published by Elsevier Ltd.)

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.

Background: The cluster randomized controlled trial on (cost-)effectiveness of integrated chronic obstructive pulmonary disease (COPD) management in primary care (RECODE) showed that integrated disease management (IDM) in primary care had no effect on quality of life (QOL) in COPD patients compared with usual care (guideline-supported non-programmatic care). It is possible that only a subset of COPD patients in primary care benefit from IDM. We therefore examined which patients benefit from IDM, and whether patient characteristics predict clinical improvement over time., Method: Post-hoc analyses of the RECODE trial among 1086 COPD patients. Logistic regression analyses were performed with baseline characteristics as predictors to examine determinants of improvement in QOL, defined as a minimal decline in Clinical COPD Questionnaire (CCQ) of 0.4 points after 12 and 24 months of IDM. We also performed moderation analyses to examine whether predictors of clinical improvement differed between IDM and usual care., Results: Regardless of treatment type, more severe dyspnea (MRC) was the most important predictor of clinically improved QOL at 12 and 24 months, suggesting that these patients have most room for improvement. Clinical improvement with IDM was associated with female gender (12-months) and being younger (24-months), and improvement with usual care was associated with having a depression (24-months)., Conclusions: More severe dyspnea is a key predictor of improved QOL in COPD patients over time. More research is needed to replicate patient characteristics associated with clinical improvement with IDM, such that IDM programs can be offered to patients that benefit the most, and can potentially be adjusted to meet the needs of other patient groups as well., Trial Registration: Netherlands Trial Register, NTR2268. Registered 31 March 2010.

Objectives: Aortic valve disease is the most frequent indication for heart valve replacement with the highest prevalence in elderly. Tissue-engineered heart valves (TEHV) are foreseen to have important advantages over currently used bioprosthetic heart valve substitutes, most importantly reducing valve degeneration with subsequent reduction of re-intervention. We performed early Health Technology Assessment of hypothetical TEHV in elderly patients (≥ 70 years) requiring surgical (SAVR) or transcatheter aortic valve implantation (TAVI) to assess the potential of TEHV and to inform future development decisions., Methods: Using a patient-level simulation model, the potential cost-effectiveness of TEHV compared with bioprostheses was predicted from a societal perspective. Anticipated, but currently hypothetical improvements in performance of TEHV, divided in durability, thrombogenicity, and infection resistance, were explored in scenario analyses to estimate quality-adjusted life-year (QALY) gain, cost reduction, headroom, and budget impact., Results: Durability of TEHV had the highest impact on QALY gain and costs, followed by infection resistance. Improved TEHV performance (- 50% prosthetic valve-related events) resulted in lifetime QALY gains of 0.131 and 0.043, lifetime cost reductions of €639 and €368, translating to headrooms of €3255 and €2498 per hypothetical TEHV compared to SAVR and TAVI, respectively. National savings in the first decade after implementation varied between €2.8 and €11.2 million (SAVR) and €3.2-€12.8 million (TAVI) for TEHV substitution rates of 25-100%., Conclusions: Despite the relatively short life expectancy of elderly patients undergoing SAVR/TAVI, hypothetical TEHV are predicted to be cost-effective compared to bioprostheses, commercially viable and result in national cost savings when biomedical engineers succeed in realising improved durability and/or infection resistance of TEHV.

Background and Aims: The efficacy of nutritional intervention to enhance short- and long-term outcomes of pulmonary rehabilitation in COPD is still unclear, hence this paper aims to investigate the clinical outcome and cost-effectiveness of a 12-month nutritional intervention strategy in muscle-wasted COPD patients., Methods: Prior to a 4-month pulmonary rehabilitation programme, 81 muscle-wasted COPD patients (51% males, aged 62.5 ± 0.9 years) with moderate airflow obstruction (FEV 1 55.1 ± 2.2% predicted) and impaired exercise capacity (W max 63.5 ± 2.4% predicted) were randomized to 3 portions of nutritional supplementation per day (enriched with leucine, vitamin D and polyunsaturated fatty acids) [NUTRITION] or PLACEBO (phase 1). In the unblinded 8-month maintenance phase (phase 2), both groups received structured feedback on their physical activity level assessed by accelerometry. NUTRITION additionally received 1 portion of supplemental nutrition per day and motivational interviewing-based nutritional counselling. A 3-month follow-up (phase 3) was included., Results: After 12 months, physical capacity measured by quadriceps muscle strength and cycle endurance time were not different, but physical activity was higher in NUTRITION than in PLACEBO (Δ1030 steps/day, p = 0.025). Plasma levels of the enriched nutrients (p < 0.001) were higher in NUTRITION than PLACEBO. Trends towards weight gain in NUTRITION and weight loss in PLACEBO led to a significant between-group difference after 12 months (Δ1.54 kg, p = 0.041). The HADS anxiety and depression scores improved in NUTRITION only (Δ-1.92 points, p = 0.037). Generic quality of life (EQ-5D) was decreased in PLACEBO but not in NUTRITION (between-group difference after 15 months 0.072 points, p = 0.009). Overall motivation towards exercising and healthy eating was high and did not change significantly after 12 months; only amotivation towards healthy eating yielded a significant between-group difference (Δ1.022 points, p = 0.015). The cost per quality-adjusted life-year after 15 months was EUR 16,750., Conclusions: Nutritional intervention in muscle-wasted patients with moderate COPD does not enhance long-term outcome of exercise training on physical capacity but ameliorates plasma levels of the supplemented nutrients, total body weight, physical activity and generic health status, at an acceptable increase of costs for patients with high disease burden., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: In health economic literature, checklists or best practice recommendations on model validation/credibility always declare verification of the programmed model as a fundamental step, such as 'is the model implemented correctly and does the implementation accurately represent the conceptual model?' However, to date, little operational guidance for the model verification process has been given. In this study, we aimed to create an operational checklist for model users or reviewers to verify the technical implementation of health economic decision analytical models and document their verification efforts., Methods: Literature on model validation, verification, programming errors and credibility was reviewed systematically from scientific databases. An initial beta version of the checklist was developed based on the checklists/tests identified from the literature and from authors' previous modeling/appraisal experience. Next, the first draft checklist was presented to a number of health economists on several occasions and was tested on different models (built in different software, developed by different stakeholders, including drug manufacturers, consultancies or academia), each time leading to an update of the checklist and culminating in the final version of the TECHnical VERification (TECH-VER) checklist, introduced in this paper., Results: The TECH-VER necessitates a model reviewer (preferably independent), an executable and transparent model, its input sources, and detailed documentation (e.g. technical report/scientific paper) in which the conceptual model, its implementation, programmed model inputs, and results are reported. The TECH-VER checklist consists of five domains: (1) input calculations; (2) event-state (patient flow) calculations; (3) result calculations; (4) uncertainty analysis calculations; and (5) other overall checks (e.g. validity or interface). The first four domains reflect the verification of the components of a typical health economic model. For these domains, as a prerequisite of verification tests, the reviewer should identify the relevant calculations in the electronic model and assess the provided justifications for the methods used in the identified calculations. For this purpose, we recommend completeness/consistency checks. Afterwards, the verification tests can be conducted for the calculations in each of these stages by checking the correctness of the implementation of these calculations. For this purpose, the following type of tests are recommended in consecutive order: (i) black-box tests, i.e. checking if model calculations are in line with a priori expectations; (ii) white-box testing, i.e. going through the program code details line by line, or cell by cell (recommended for some crucial calculations and if there are some unexpected results from the black-box tests); and (iii) model replication/parallel programming (recommended only in certain situations, and if the issues related to the identified unexpected results from black-box tests could not be resolved through white-box testing). To reduce the time burden of model verification, we suggest a hierarchical order in tests i-iii, where going to the next step is necessary when the previous step fails., Conclusions: The TECH-VER checklist is a comprehensive checklist for the technical verification of decision analytical models, aiming to help identify model implementation errors and their root causes while improving the transparency and efficiency of the verification efforts. In addition to external reviews, we consider that the TECH-VER can be used as an internal training and quality control tool for new health economists, while developing their initial models. It is the authors' aim that the TECH-VER checklist transforms itself to an open-source living document, with possible future versions, or 'bolt-on' extensions for specific applications with additional 'fit-for-purpose' tests, as well as 'tips and tricks' and some demonstrative error examples. For this reason, the TECH-VER checklist and the list of black-box tests created in this paper and a few model verification examples is uploaded to an open access, online platform (github and the website of the institute), where other users will also be able to upload their original verification efforts and tests.

Background: As a living heart valve substitute with growth potential and improved durability, tissue-engineered heart valves (TEHVs) may prevent reinterventions that are currently often needed in children with congenital heart disease. We performed early health technology assessment to assess the potential cost-effectiveness of TEHVs in children requiring right ventricular outflow tract reconstruction (RVOTR)., Methods: A systematic review and meta-analysis was conducted of studies reporting clinical outcome after RVOTR with existing heart valve substitutes in children (mean age ≤12 years or maximum age ≤21 years) published between January 1, 2000, and May 2, 2018. Using a patient-level simulation model, costs and effects of RVOTR with TEHVs compared with existing heart valve substitutes were assessed from a health care perspective applying a 10-year time horizon. Improvements in performance of TEHVs, divided in durability, thrombogenicity, and infection resistance, were explored to estimate quality-adjusted life year (QALY) gain, cost reduction, headroom, and budget impact associated with TEHVs., Results: Five-year freedom from reintervention after RVOTR with existing heart valve substitutes was 46.1% in patients less than or equal to 2 years of age and 81.1% in patients greater than 2 years of age. Improvements in durability had the highest impact on QALYs and costs. In the improved TEHV performance scenario (durability ≥5 years and -50% other valve-related events), QALY gain was 0.074 and cost reduction was €10,378 per patient, translating to maximum additional costs of €11,856 per TEHV compared with existing heart valve substitutes., Conclusions: This study showed that there is room for improvement in clinical outcomes in children requiring RVOTR. If TEHVs result in improved clinical outcomes, they are expected to be cost-effective compared with existing heart valve substitutes., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: To support decision-making in aortic valve replacement (AVR) in elderly patients, we provide a comprehensive overview of outcome after AVR with bioprostheses., Methods: A systematic review was conducted of studies reporting clinical outcome after AVR with bioprostheses in elderly patients (mean age ≥70 years; minimum age ≥65 years) published between January 1, 2000, to September 1, 2016. Reported event rates and time-to-event data were pooled and entered into a microsimulation model to calculate life expectancy and lifetime event risks., Results: Forty-two studies reporting on 34 patient cohorts were included, encompassing a total of 12,842 patients with 55,437 patient-years of follow-up (pooled mean follow-up 5.0 ± 3.3 years). Pooled mean age was 76.5 ± 5.5 years. Pooled early mortality risk was 5.42% (95% confidence interval [CI], 4.49-6.55), thromboembolism rate was 1.83%/year (95% CI, 1.28-3.61), and bleeding rate was 0.75%/year (95% CI, 0.50-1.11). Structural valve deterioration (SVD) was based on pooled time to SVD data (Gompertz; shape: 0.124, rate: 0.003). For a 75-year-old patient, this translated to an estimated life expectancy of 9.8 years (general population: 10.2 years) and lifetime risks of bleeding of 7%, thromboembolism of 17%, and reintervention of 9%., Conclusions: The low risks of SVD and reintervention support the use of bioprostheses in elderly patients in need of AVR. The estimated life expectancy after AVR was comparable with the general population. The results of this study inform patients and clinicians about the expected outcomes after bioprosthetic AVR and thereby support treatment decision-making. Furthermore, our results can be used as a benchmark for long-term outcomes after transcatheter aortic valve implantation in patients who were eligible for surgery and other (future) alternative treatments (eg, tissue-engineered heart valves)., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

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.

Background In discrete-choice experiments (DCEs), choice alternatives are described by attributes. The importance of each attribute can be quantified by analyzing respondents' choices. Estimates are valid only if alternatives are defined comprehensively, but choice tasks can become too difficult for respondents if too many attributes are included. Several solutions for this dilemma have been proposed, but these have practical or theoretical drawbacks and cannot be applied in all settings. The objective of the current article is to demonstrate an alternative solution, the fold-in, fold-out approach (FiFo). We use a motivating example, the ABC Index for burden of disease in chronic obstructive pulmonary disease (COPD). Methods Under FiFo, all attributes are part of all choice sets, but they are grouped into domains. These are either folded in (all attributes have the same level) or folded out (levels may differ). FiFo was applied to the valuation of the ABC Index, which included 15 attributes. The data were analyzed in Bayesian mixed logit regression, with additional parameters to account for increased complexity in folded-out questionnaires and potential differences in weight due to the folding status of domains. As a comparison, a model without the additional parameters was estimated. Results Folding out domains led to increased choice complexity for respondents. It also gave domains more weight than when it was folded in. The more complex regression model had a better fit to the data than the simpler model. Not accounting for choice complexity in the models resulted in a substantially different ABC Index. Conclusion Using a combination of folded-in and folded-out attributes is a feasible approach for conducting DCEs with many attributes.

Objectives: Our aim was to provide estimates of patient-reported health-related quality of life (HRQoL), use of informal care and productivity in patients after surgical aortic and pulmonary valve replacement and transcatheter aortic valve implantation., Methods: Consecutive cohorts of 1239 adult patients who had surgical aortic valve replacement or surgical pulmonary valve replacement and 433 patients who had transcatheter aortic valve implantation at 2 Dutch heart centres were cross-sectionally surveyed at a median time of 2.9 and 3.2 years after the intervention, respectively. The survey included questions on HRQoL (EQ-5D-5L and SF-12-v2), use of informal care and productivity in paid and unpaid work. All outcomes were compared with age and sex-matched individuals from the general population., Results: The response rate was 56% (n = 687) of patients who had surgical valve replacement and 59% (n = 257) of those who had transcatheter aortic valve implantation. Compared with the general population, patients reported poorer HRQoL on physical health domains, whereas their scores were comparable for mental health domains. After a heart valve implantation, patients reported using informal care more frequently than the general population, but labour participation was comparable. Patients with late complications [antibiotic treatment for endocarditis (n = 4), stroke (n = 11), transient ischaemic attack (n = 15)] reported lower HRQoL, greater use of informal care and greater productivity loss than patients without complications., Conclusions: Patients who had aortic and pulmonary valve implantations experience relatively mild limitations in daily life compared to the general population. The consequences of a heart valve implantations beyond clinical outcomes should be considered to create realistic patient expectations of life after a heart valve implantation and unbiased resource allocation decisions at national levels., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

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., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: OnkoNetwork is a recently established integrated care model with a personalized pathway system to manage patients with first suspect of a solid tumour in secondary care, that evolved as a regional initiative in Hungary. The primary aim of OnkoNetwork is the improvement of clinical outcomes via timely access to quality assured and defragmented healthcare services. The Horizon 2020 funded SELFIE project has selected OnkoNetwork for in-depth qualitative and quantitative evaluation. The aim of this study was to provide a qualitative evaluation of OnkoNetwork along the six components of the SELFIE conceptual framework: 1) service delivery, 2) leadership and governance, 3) workforce, 4) financing, 5) technologies and medical products, and 6) information and research., Methods: Analysis of published and grey programme documentation, followed by 20 semi-structured interviews with representatives of programme initiators, general and financial managers, involved physicians and non-physician professionals, patients and their informal caregivers. Transcripts of all interviews were analysed by Mayring's content analysis method by two independent researchers., Results: This study yielded the first comprehensive description of the programme. OnkoNetwork is a blue dahila in Central and Eastern Europe, providing timely and quality-assured healthcare services for the target patients by personalized patient path monitoring and management in a financially sustainable manner without macro-level financing of its operation. Innovative professional roles were implemented for non-physicians and physicians, and a supporting information technology application was developed., Conclusions: This paper provides a systematic description of OnkoNetwork on the six components of the SELFIE conceptual framework for integrated care in multimorbidity to understand how and why OnkoNetwork was implemented and cares (better) for its patients. Because integrated care models are designed and adjusted to their specific local needs and context, those few successful and sustainable models that were established in Central and Eastern European countries represent important benchmarks for other initiatives in this region. Experience with OnkoNetwork during its planning, implementation and operation including the description of key success factors and barriers as perceived by various stakeholder groups, may support the development of further integrated care models especially in countries with similar economic status and healthcare settings.

The objective of this study was to evaluate current approaches to economic modeling in rheumatoid arthritis (RA) and propose a new conceptual model for evaluation of the cost-effectiveness of RA interventions. We followed recommendations from the International Society of Pharmacoeconomics and Outcomes Research-Society of Medical Decision Making (ISPOR-SMDM) Modeling Good Research Practices Task Force-2. The process involved scoping the decision problem by a working group and drafting a preliminary cost-effectiveness model framework. A systematic literature review (SLR) of existing decision-analytic models was performed and analysis of an RA registry was conducted to inform the structure of the draft conceptual model. Finally, an expert panel was convened to seek input on the draft conceptual model. The proposed conceptual model consists of three separate modules: 1) patient characteristic module, 2) treatment module, and 3) outcome module. Consistent with the scope, the conceptual model proposed six changes to current economic models in RA. These changes proposed are to: 1) use composite measures of disease activity to evaluate treatment response as well as disease progression (at least two measures should be considered, one as the base case and one as a sensitivity analysis); 2) conduct utility mapping based on disease activity measures; 3) incorporate subgroups based on guideline-recommended prognostic factors; 4) integrate realistic treatment patterns based on clinical practice/registry datasets; 5) assimilate outcomes that are not joint related (extra-articular outcomes); and 6) assess mortality based on disease activity. We proposed a conceptual model that incorporates the current understanding of clinical and real-world evidence in RA, as well as of existing modeling assumptions. The proposed model framework was reviewed with experts and could serve as a foundation for developing future cost-effectiveness models in RA., Competing Interests: E. Alemao is an employee of BMS, a manufacturer of biologic disease modifying anti-rheumatic medication. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Objectives: The prevalence of multimorbidity is increasing in many Western countries. Persons with multimorbidity often experience a lack of alignment in the care that multiple health and social care organisations provide. As a response, integrated care programmes are appearing. It is a challenge to evaluate these and to choose appropriate outcome measures. Focus groups were held with persons with multimorbidity in eight European countries to better understand what good health and a good care process mean to them and to identify what they find most important in each., Methods: In 2016, eight focus groups were organised with persons with multimorbidity in: Austria, Croatia, Germany, Hungary, the Netherlands, Norway, Spain and the UK (total n=58). Each focus group followed the same two-part procedure: (1) defining (A) good health and well-being and (B) a good care process, and (2) group discussion on prioritising the most important concepts derived from part one and from a list extracted from the literature. Inductive and deductive analyses were done., Results: Overall, the participants in all focus groups concentrated more on the care process than on health. Persons with multimorbidity defined good health as being able to conduct and plan normal daily activities, having meaningful social relationships and accepting the current situation. Absence of shame, fear and/or stigma, being able to enjoy life and overall psychological well-being were also important facets of good health. Being approached holistically by care professionals was said to be vital to a good care process. Continuity of care and trusting professionals were also described as important. Across countries, little variation in health definitions were found, but variation in defining a good care process was seen., Conclusion: A variety of health outcomes that entail well-being, social and psychological facets and especially experience with care outcomes should be included when evaluating integrated care programmes for persons with multimorbidity., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

Objective: To review the evidence on the cost-effectiveness of heart valve implantations generated by decision analytic models and to assess their methodological quality., Methods: A systematic review was performed including model-based cost-effectiveness analyses of heart valve implantations. Study and model characteristics and cost-effectiveness results were extracted and the methodological quality was assessed using the Philips checklist., Results: Fourteen decision-analytic models regarding the cost-effectiveness of heart valve implantations were identified. In most studies transcatheter aortic valve implantation (TAVI) was cost-effective compared to standard treatment (ST) in inoperable or high-risk operable patients (ICER range 18,421-120,779 €) and in all studies surgical aortic valve replacement (SAVR) was cost-effective compared to ST in operable patients (ICER range 14,108-40,944 €), but the results were not consistent on the cost-effectiveness of TAVI versus SAVR in high-risk operable patients (ICER range: dominant to dominated by SAVR). Mechanical mitral valve replacement (MVR) had the lowest costs per success compared to mitral valve repair and biological MVR. The methodological quality of the studies was moderate to good., Conclusion: This review showed that improvements can be made in the description and justification of methods and data sources, sensitivity analysis on extrapolation of results, subgroup analyses, consideration of methodological and structural uncertainty, and consistency (i.e. validity) of the models. There are several opportunities for future decision-analytic models of the cost-effectiveness of heart valve implantations: considering heart valve implantations in other valve positions besides the aortic valve, using a societal perspective, and developing patient-simulation models to investigate the impact of patient characteristics on outcomes.

Objective: In the era of limited healthcare budgets, healthcare costs of heart valve implantations need to be considered to inform cost-effectiveness analyses. We aimed to provide age group-specific costs estimates of heart valve implantations, related complications and other healthcare utilisation following the intervention., Methods: We performed retrospective analyses of healthcare costs of patients who had undergone heart valve implantations in 2010-2013 and controls using claims data from Dutch health insurers. Heart valve implantations included surgical valve replacement and transcatheter valve implantation in all heart valve positions. Patients were divided in four age groups. Control groups were created by taking random samples of the Dutch population stratified by age, gender, socioeconomic status and comorbidities. We applied non-parametric bootstrapping to address uncertainty of the cost estimates. The association of patient and intervention characteristics with costs was determined by (multilevel) generalised linear models., Results: The baseline characteristics of 18 903 patients and 188 925 controls were comparable. The annual healthcare costs were substantially higher for surgical heart valve replacement patients than for controls, especially in the year of heart valve implantation. Factors associated with increased annual healthcare costs for patients were older age, female gender, comorbidities, low socioeconomic status and complications., Conclusions: We provided a comprehensive overview of age group-specific incidence of heart valve implantations, subsequent survival and complications as well as associated healthcare costs of all patients in the Netherlands. Our results provide real-world costs estimates that can be used as a benchmark for costs of future innovative heart valve implantations., Competing Interests: Competing interests: None declared.

Objective: The Assessment of Burden of COPD (ABC) tool supports shared decision making between patient and caregiver. It includes a coloured balloon diagram to visualise patients' scores on burden indicators. We aim to determine the importance of each indicator from a patient perspective, in order to calculate a weighted index score and investigate whether that score is predictive of costs., Design: Discrete choice experiment., Setting and Participants: Primary care and secondary care in the Netherlands. 282 patients with chronic obstructive pulmonary disease (COPD) and 252 members of the general public participated., Methods: Respondents received 14 choice questions and indicated which of two health states was more severe. Health states were described in terms of specific symptoms, limitations in physical, daily and social activities, mental problems, fatigue and exacerbations, most of which had three levels of severity. Weights for each item-level combination were derived from a Bayesian mixed logit model. Weights were rescaled to construct an index score from 0 (best) to 100 (worst). Regression models were used to find a classification of this index score in mild, moderate and severe that was discriminative in terms of healthcare costs., Results: Fatigue, limitations in moderate physical activities, number of exacerbations, dyspnoea at rest and fear of breathing getting worse contributed most to the burden of disease. Patients assigned less weight to dyspnoea during exercise, listlessness and limitations with regard to strenuous activities. Respondents from the general public mostly agreed. Mild, moderate and severe burden of disease were defined as scores <20, 20-39 and ≥40. This categorisation was most predictive of healthcare utilisation and annual costs: €1368, €2510 and €9885, respectively., Conclusions: The ABC I ndex is a new index score for the burden of COPD, which is based on patients' preferences. The classification of the index score into mild, moderate and severe is predictive of future healthcare costs., Trial Registration Number: NTR3788; Post-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: To describe the adaptation of a global health economic model to determine whether treatment with the angiotensin receptor neprilysin inhibitor LCZ696 is cost effective compared with the angiotensin-converting enzyme inhibitor enalapril in adult patients with chronic heart failure with reduced left ventricular ejection fraction in the Netherlands; and to explore the effect of performing the cost-effectiveness analyses according to the new pharmacoeconomic Dutch guidelines (updated during the submission process of LCZ696), which require a value-of-information analysis and the inclusion of indirect medical costs of life-years gained., Methods: We adapted a UK model to reflect the societal perspective in the Netherlands by including travel expenses, productivity loss, informal care costs, and indirect medical costs during the life-years gained and performed a preliminary value-of-information analysis., Results: The incremental cost-effectiveness ratio obtained was €17,600 per quality-adjusted life-year (QALY) gained. This was robust to changes in most structural assumptions and across different subgroups of patients. Probability sensitivity analysis results showed that the probability that LCZ696 is cost-effective at a €50,000 per QALY threshold is 99.8%, with a population expected value of perfect information of €297,128. On including indirect medical costs of life-years gained, the incremental cost-effectiveness ratio was €26,491 per QALY gained, and LCZ696 was 99.46% cost effective at €50,000 per QALY, with a population expected value of perfect information of €2,849,647., Conclusions: LCZ696 is cost effective compared with enalapril under the former and current Dutch guidelines. However, the (monetary) consequences of making a wrong decision were considerably different in both scenarios., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: To develop statistical models predicting disease progression and outcomes in chronic obstructive pulmonary disease (COPD), using data from ECLIPSE, a large, observational study of current and former smokers with COPD., Methods: Based on a conceptual model of COPD disease progression and data from 2164 patients, associations were made between baseline characteristics, COPD disease progression attributes (exacerbations, lung function, exercise capacity, and symptoms), health-related quality of life (HRQoL), and survival. Linear and nonlinear functional forms of random intercept models were used to characterize these relationships. Endogeneity was addressed by time-lagging variables in the regression models., Results: At the 5% significance level, an exacerbation history in the year before baseline was associated with increased risk of future exacerbations (moderate: +125.8%; severe: +89.2%) and decline in lung function (forced expiratory volume in 1 second [FEV 1 ]) (-94.20 mL per year). Each 1% increase in FEV 1 % predicted was associated with decreased risk of exacerbations (moderate: -1.1%; severe: -3.0%) and increased 6-minute walk test distance (6MWD) (+1.5 m). Increases in baseline exercise capacity (6MWD, per meter) were associated with slightly increased risk of moderate exacerbations (+0.04%) and increased FEV 1 (+0.62 mL). Symptoms (dyspnea, cough, and/or sputum) were associated with an increased risk of moderate exacerbations (+13.4% to +31.1%), and baseline dyspnea (modified Medical Research Council score ≥2 v. <2) was associated with lower FEV 1 (-112.3 mL)., Conclusions: A series of linked statistical regression equations have been developed to express associations between indicators of COPD disease severity and HRQoL and survival. These can be used to represent disease progression, for example, in new economic models of COPD.

Background: The recent joint International Society for Pharmacoeconomics and Outcomes Research / Society for Medical Decision Making Modeling Good Research Practices Task Force emphasized the importance of conceptualizing and validating models. We report a new model of chronic obstructive pulmonary disease (COPD) (part of the Galaxy project) founded on a conceptual model, implemented using a novel linked-equation approach, and internally validated., Methods: An expert panel developed a conceptual model including causal relationships between disease attributes, progression, and final outcomes. Risk equations describing these relationships were estimated using data from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, with costs estimated from the TOwards a Revolution in COPD Health (TORCH) study. Implementation as a linked-equation model enabled direct estimation of health service costs and quality-adjusted life years (QALYs) for COPD patients over their lifetimes. Internal validation compared 3 years of predicted cohort experience with ECLIPSE results., Results: At 3 years, the Galaxy COPD model predictions of annual exacerbation rate and annual decline in forced expiratory volume in 1 second fell within the ECLIPSE data confidence limits, although 3-year overall survival was outside the observed confidence limits. Projections of the risk equations over time permitted extrapolation to patient lifetimes. Averaging the predicted cost/QALY outcomes for the different patients within the ECLIPSE cohort gives an estimated lifetime cost of £25,214 (undiscounted)/£20,318 (discounted) and lifetime QALYs of 6.45 (undiscounted/5.24 [discounted]) per ECLIPSE patient., Conclusions: A new form of model for COPD was conceptualized, implemented, and internally validated, based on a series of linked equations using epidemiological data (ECLIPSE) and cost data (TORCH). This Galaxy model predicts COPD outcomes from treatment effects on disease attributes such as lung function, exacerbations, symptoms, or exercise capacity; further external validation is required.

Background: To develop and validate a new conceptual model (CM) of chronic obstructive pulmonary disease (COPD) for use in disease progression and economic modeling. The CM identifies and describes qualitative associations between disease attributes, progression and outcomes., Methods: A literature review was performed to identify any published CMs or literature reporting the impact and association of COPD disease attributes with outcomes. After critical analysis of the literature, a Steering Group of experts from the disciplines of health economics, epidemiology and clinical medicine was convened to develop a draft CM, which was refined using a Delphi process. The refined CM was validated by testing for associations between attributes using data from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE)., Results: Disease progression attributes included in the final CM were history and occurrence of exacerbations, lung function, exercise capacity, signs and symptoms (cough, sputum, dyspnea), cardiovascular disease comorbidities, 'other' comorbidities (including depression), body composition (body mass index), fibrinogen as a biomarker, smoking and demographic characteristics (age, gender). Mortality and health-related quality of life were determined to be the most relevant final outcome measures for this model, intended to be the foundation of an economic model of COPD., Conclusion: The CM is being used as the foundation for developing a new COPD model of disease progression and to provide a framework for the analysis of patient-level data. The CM is available as a reference for the implementation of further disease progression and economic models.

Background: Worldwide, chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic lung disease with considerable clinical and socioeconomic impact. Pharmacologic maintenance drugs (such as bronchodilators and inhaled corticosteroids) play an important role in the treatment of COPD. The cost effectiveness of these treatments has been frequently assessed, but studies to date have largely neglected the impact of treatment sequence and the exact stage of disease in which the drugs are used in real life., Objective: We aimed to systematically review recently published articles that reported the cost effectiveness of COPD maintenance treatments, with a focus on key findings, quality and methodological issues., Methods: We performed a systematic literature search in Embase, PubMed, the UK NHS Economic Evaluation Database (NHS-EED) and EURONHEED (European Network of Health Economics Evaluation Databases) and included all relevant articles published between 2011 and 2015 in either Dutch, English or German. Main study characteristics, methods and outcomes were extracted and critically assessed. The Quality of Health Economic Studies (QHES) instrument was used as basis for quality assessment, but additional items were also addressed., Results: The search identified 18 recent pharmacoeconomic analyses of COPD maintenance treatments. Papers reported the cost effectiveness of long-acting muscarinic antagonist (LAMA) monotherapy (n = 6), phosphodiesterase (PDE)-4 inhibitors (n = 4), long-acting beta agonist/inhaled corticosteroid (LABA/ICS) combinations (n = 4), LABA monotherapy (n = 2) and LABA/LAMA combinations (n = 2). All but two studies were funded by the manufacturer, and all studies indicated favourable cost effectiveness; however, the number of quality-adjusted life-years (QALYs) gained was small. Less than half of the studies reported a COPD-specific outcome in addition to a generic outcome (mostly QALYs). Exacerbation and mortality rates were found to be the main drivers of cost effectiveness. According to the QHES, the quality of the studies was generally sufficient, but additional assessment revealed that most studies poorly represented the cost effectiveness of real-life medication use., Conclusions: The majority of studies showed that pharmacologic COPD maintenance treatment is cost effective, but most studies poorly reflected real-life drug use. Consistent and COPD-specific methodology is recommended., Competing Interests: Compliance with Ethical Standards Competing interests SvdS has no competing interests. JvB, JK and MJP are employed at the University of Groningen, which has received research grants from Boehringer Ingelheim, AstraZeneca and GlaxoSmithKline, all manufacturers of some of the respiratory drugs described in this article. JK has received several research grants and has been paid for consultancy services by AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline and Novartis, companies that produce drugs reviewed in this paper. MJP has received grants and honoraria from various pharmaceutical companies, including those developing, producing and marketing COPD drugs. MRM, LG and MB are employed by the Erasmus University Rotterdam, which has received research grants from Boehringer Ingelheim, GlaxoSmithKline, Novartis, AstraZeneca, Chiesi, and Almirall, manufacturers of respiratory drugs. Funding No funding was received for this study.

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 [FEV 1 ] % 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 FEV 1 % 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 FEV 1 % 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., (Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)