Cost-effectiveness of alternative NTRK testing strategies in cancer patients followed by histology-independent therapy with entrectinib: an analysis of three European countries.

Aim: To explore variations in the cost-effectiveness of entrectinib across different testing strategies and settings. Methods: Four testing strategies where adult cancer patients received entrectinib if they tested positive for NTRK gene fusions compared with 'no testing' and standard of care (SoC) for all patients were evaluated. Results: Immunohistochemistry for all patients followed by RNA-based next-generation sequencing after a positive result was the optimal strategy in all included countries. However, the incremental net monetary benefit compared with SoC was negative in all countries, ranging between international euros (int€) -206 and -404. In a subgroup analysis with only NTRK-positive patients, the incremental net monetary benefit was int€ 8405 in England, int€ -53,088 in Hungary and int€ 54,372 in The Netherlands. Conclusion: Using the cost-effectiveness thresholds recommended by national guidelines, none of the testing strategies were cost-effective compared with no testing. The implementation of entrectinib is unlikely to become cost-effective in Hungary, due to the large cost difference between the entrectinib and SoC arms, while there might be more potential in England and The Netherlands.

Histology-independent pharmaceuticals are a new phenomenon in cancer care. Most chemotherapies are prescribed based on the tumor's (primary) location, while histology-independent therapies are prescribed based on genetic markers in the tumor DNA. In this study, the added value of the histology-independent treatment entrectinib, which is aimed at cancer patients with so-called NTRK gene fusions, was investigated. Because these patients must be identified before they can be given entrectinib, various strategies for diagnostic testing were considered. An economic model was programmed to gain insight into the costs and health outcomes associated with the different testing strategies. The same analysis was done for three different countries (England, Hungary and The Netherlands) using local data. In all three countries, the health gains from receiving entrectinib may be large for patients with NTRK gene fusions. However, treatment with entrectinib was also much more expensive than standard-care treatment, especially in Hungary. In each of the three countries, all evaluated testing strategies were found to offer a negative net benefit to society (i.e., a net loss). This may be partially explained by the fact that NTRK gene fusions are rare, meaning that a large group of cancer patients has to receive (costly) testing while, subsequently, only a few patients enjoy the benefit of switching to a treatment that is more effective for them (i.e., entrectinib). Nonetheless, in England and Hungary, even if the most accurate test was provided for free, the net benefit to society of implementing entrectinib remained negative. Further changes, such as a reduction in the price of entrectinib, may therefore be needed.

Cost-Effectiveness Analysis of Treating Patients With NTRK-Positive Cancer With the Histology-Independent Therapy Entrectinib.

OBJECTIVES: This study tackles several challenges of evaluating histology-independent treatments using entrectinib as an example. Histology-independent treatments are provided based on genetic marker(s) of tumors, regardless of the tumor type. We evaluated the lifetime cost-effectiveness of testing all patients for NTRK fusions and treating the positive cases with entrectinib compared with no testing and standard of care (SoC) for all patients. METHODS: The health economic model consisted of a decision tree reflecting the NTRK testing phase followed by a microsimulation model reflecting treatment with either entrectinib or SoC. Efficacy of entrectinib was based on data from basket trials, whereas historical data from NTRK-negative patients were corrected for the prognostic value of NTRK fusions to model SoC. RESULTS: "Testing" (testing for NTRK fusions, with subsequent entrectinib treatment in NTRK-positive patients and SoC in NTRK-negative patients) had higher per-patient quality-adjusted life-years (QALYs) and costs than "No testing" (SoC for all patients), with a difference of 0.0043 and €732, respectively. This corresponded to an incremental cost-effectiveness ratio (ICER) of €169 957/QALY and, using a cost-effectiveness threshold of €80 000/QALY, an incremental net monetary benefit of -€388. When excluding the costs of genetic testing for NTRK fusions, the ICER was reduced to €36 290/QALY and the incremental net monetary benefit increased to €188. CONCLUSIONS: When treatment requires the identification of a genetic marker, the associated costs and effects need to be accounted for. Because of the low prevalence of NTRK fusions, the number needed-to-test to identify patients eligible for entrectinib is large. Excluding the testing phase reduces the ICER substantially.

Stratification of COPD patients towards personalized medicine: reproduction and formation of clusters.

BACKGROUND: The global initiative for chronic obstructive lung disease (GOLD) 2020 emphasizes that there is only a weak correlation between FEV1, symptoms and impairment of the health status of patients with chronic obstructive pulmonary disease (COPD). Various studies aimed to identify COPD phenotypes by cluster analyses, but behavioral aspects besides smoking were rarely included. METHODS: The aims of the study were to investigate whether (i) clustering analyses are in line with the classification into GOLD ABCD groups; (ii) clustering according to Burgel et al. (Eur Respir J. 36(3):531-9, 2010) can be reproduced in a real-world COPD cohort; and (iii) addition of new behavioral variables alters the clustering outcome. Principal component and hierarchical cluster analyses were applied to real-world clinical data of COPD patients newly referred to secondary care (n = 155). We investigated if the obtained clusters paralleled GOLD ABCD subgroups and determined the impact of adding several variables, including quality of life (QOL), fatigue, satisfaction relationship, air trapping, steps per day and activities of daily living, on clustering. RESULTS: Using the appropriate corresponding variables, we identified clusters that largely reflected the GOLD ABCD groups, but we could not reproduce Burgel's clinical phenotypes. Adding six new variables resulted in the formation of four new clusters that mainly differed from each other in the following parameters: number of steps per day, activities of daily living and QOL. CONCLUSIONS: We could not reproduce previously identified clinical COPD phenotypes in an independent population of COPD patients. Our findings therefore indicate that COPD phenotypes based on cluster analysis may not be a suitable basis for treatment strategies for individual patients.

Improved survival of non-small cell lung cancer patients after introducing patient navigation: A retrospective cohort study with propensity score weighted historic control.

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.

Prioritization of implementation barriers related to integrated care models in Central and Eastern European countries.

The importance of integrated care will increase in future health systems due to aging populations and patients with chronic multimorbidity, however, such complex healthcare interventions are often developed and implemented in higher income countries. For Central and Eastern European (CEE) countries it is important to investigate which integrated care models are transferable to their setting and facilitate the implementation of relevant models by identifying barriers to their implementation. This study investigates the relative importance of integrated care models and the most critical barriers for their implementation in CEE countries. Experts from Croatia, Hungary, Poland, Romania and Serbia were invited to complete an online survey within the SELFIE H2020 project. 81 respondents completed the survey. Although experts indicated that some integrated care models were already being implemented in CEE countries, the survey revealed a great need for further improvement in the integration of care, especially the managed care of oncology patients, coordinated palliative care of terminally ill patients, and nursing care of elderly with multimorbidity. Lack of long-term financial sustainability as well as of dedicated financing schemes were seen the most critical implementation barriers, followed by the lack of integration between health and social care providers and insufficient availability of human resources. These insights can guide future policy making on integrated care in CEE countries.

Moving Beyond Quality-Adjusted Life-Years in Elderly Care: How Can Multicriteria Decision Analysis Complement Cost-Effectiveness Analysis in Local-Level Decision Making.

OBJECTIVES: This study aimed to investigate how multicriteria decision analysis (MCDA) could complement cost-effectiveness analysis (CEA) to support investment decisions in elderly care at local level. METHODS: We used an integrated elderly care program in The Netherlands as a case study to demonstrate the application of both methods. In a 12-month quasi-experimental study (n = 384), data on the following outcome measures were collected: quality-adjusted life-years (CEA) and physical functioning, psychological well-being, social relationships and participation, enjoyment of life, resilience, person centeredness, continuity of care, and costs (MCDA). We performed regression analysis on inversed probability weighted data and controlled for potential confounders to obtain a double robust estimate of the outcomes. Probabilistic sensitivity analyses determined uncertainty for both methods. RESULTS: The integrated elderly care program was not likely (ie, 36%) to be cost-effective according to the CEA (incremental cost-effectiveness ratios: €88 249 from a societal perspective) using the conventional Dutch willingness-to-pay threshold (ie, €50 000). The MCDA demonstrated that informal caregivers and professionals slightly preferred the intervention over usual care, driven by enjoyment of life and person centeredness. Patients did not prefer either the intervention or usual care, whereas payers and policy makers slightly preferred usual care, mainly due to higher costs of the intervention. CONCLUSIONS: MCDA could provide local-level decision makers with a broader measurement of effectiveness by including outcomes beyond health and longevity and the preferences of multiple stakeholders. This additional information could foster the acceptability and implementability of cost-effective innovations in elderly care.

Value-based person-centred integrated care for frail elderly living at home: a quasi-experimental evaluation using multicriteria decision analysis.

OBJECTIVE: To evaluate the value of the person-centred, integrated care programme Care Chain Frail Elderly (CCFE) compared with usual care, using multicriteria decision analysis (MCDA). DESIGN: In a 12-month quasi-experimental study, triple-aim outcomes were measured at 0, 6 and 12 months by trained interviewers during home-visits. SETTING: Primary care, community-based elderly care. PARTICIPANTS: 384 community-dwelling frail elderly were enrolled. The 12-month completion rate was 70% in both groups. Propensity score matching was used to balance age, gender, marital status, living situation, education, smoking status and 3 month costs prior to baseline between the two groups. INTERVENTION: The CCFE is an integrated care programme with unique features like the presence of the elderly and informal caregiver at the multidisciplinary team meetings, and a bundled payment. PRIMARY AND SECONDARY OUTCOMES MEASURES: The MCDA results in weighted overall value scores that combines the performance on physical functioning, psychological well-being, social relationships and participation, enjoyment of life, resilience, person-centredness, continuity of care and costs, with importance weights of patients, informal caregivers, professionals, payers and policy-makers. RESULTS: At 6 months, the overall value scores of CCFE were higher in all stakeholder groups, driven by enjoyment of life (standardised performance scores 0.729 vs 0.685) and person-centredness (0.749 vs 0.663). At 12 months, the overall value scores in both groups were similar from a patient's perspective, slightly higher for CCFE from an informal caregiver's and professional's perspective, and lower for CCFE from a payer's and policy-maker's perspective. The latter was driven by a worse performance on physical functioning (0.682 vs 0.731) and higher costs (€22 816 vs €20 680). CONCLUSIONS: The MCDA indicated that the CCFE is the preferred way of delivering care to frail elderly at 6 months. However, at 12 months, MCDA results showed little difference from the perspective of patients, informal caregivers and professionals, while payers and policy-makers seemed to prefer usual care.

The Net Benefit of Personalized Medicine: A Systematic Literature Review and Regression Analysis.

OBJECTIVES: Amidst conflicting expectations about the benefits of personalized medicine (PM) and the potentially high implementation costs, we reviewed the available evidence on the cost-effectiveness of PM relative to non-PM. METHODS: We conducted a systematic literature review of economic evaluations of PM and extracted data, including incremental quality-adjusted life-years (ΔQALYs) and incremental costs (Δcosts). ΔQALYs and Δcosts were combined with estimates of national cost-effectiveness thresholds to calculate incremental net monetary benefit (ΔNMB). Regression analyses were performed with these variables as dependent variables and PM intervention characteristics as independent variables. Random intercepts were used to cluster studies according to country. RESULTS: Of 4774 studies reviewed, 128 were selected, providing cost-effectiveness data for 279 PM interventions. Most studies were set in the United States (48%) and the United Kingdom (16%) and adopted a healthcare perspective (82%). Cancer treatments (60%) and pharmaceutical interventions (72%) occurred frequently. Prognostic tests (19%) and tests to identify (non)responders (37%) were least and most common, respectively. Industry sponsorship occurred in 32%. Median ΔQALYs, Δcosts, and ΔNMB per individual were 0.03, Int$575, and Int$18, respectively. We found large heterogeneity in cost-effectiveness. Regression analysis showed that gene therapies were associated with higher ΔQALYs than other interventions. PM interventions for neoplasms brought higher ΔNMB than PM interventions for other conditions. Nonetheless, average ΔNMB in the 'neoplasm' group was found to be negative. CONCLUSIONS: PM brings improvements in health but often at a high cost, resulting in 0 to negative ΔNMB on average. Pricing policies may be needed to reduce the costs of interventions with negative ΔNMB.

Early palliative care associated with lower costs for adults with advanced cancer: evidence from Hungary.

OBJECTIVE: Palliative Care Consult Service (PCCS) programme was established in Hungary to provide palliative care to hospitalised patients with complex needs and to coordinate integrated care across providers. The aim of this study was to measure the association of PCCS with healthcare costs from payer's perspective. METHODS: Study population consisted of patients with metastatic cancer, who were admitted to the Clinical Centre of the University of Pécs between 2014 and 2016. Patients who did not die within 180 days from enrolment were excluded. Patients receiving services from PCCS team (intervention patients) were compared to patients receiving usual care (controls). The two populations were matched using propensity scores. Data were obtained from electronic medical records linked to claims data. RESULTS: For patients who were involved in PCCS at least 60 days before their death, the costs of care outside the acute hospital were higher. However, this was offset by savings in hospital costs so that the total healthcare cost was significantly reduced (p = 0.034). The proportion of patients who died in the hospital was lower in the PCCS group compared to the usual care group (66% vs. 85%, p = 0.022). CONCLUSION: Timely initiation of palliative care for hospitalised patients is associated with cost savings for the healthcare system.

Evaluation of integrated care services in Catalonia: population-based and service-based real-life deployment protocols.

BACKGROUND: Comprehensive assessment of integrated care deployment constitutes a major challenge to ensure quality, sustainability and transferability of both healthcare policies and services in the transition toward a coordinated service delivery scenario. To this end, the manuscript articulates four different protocols aiming at assessing large-scale implementation of integrated care, which are being developed within the umbrella of the regional project Nextcare (2016-2019), undertaken to foster innovation in technologically-supported services for chronic multimorbid patients in Catalonia (ES) (7.5 M inhabitants). Whereas one of the assessment protocols is designed to evaluate population-based deployment of care coordination at regional level during the period 2011-2017, the other three are service-based protocols addressing: i) Home hospitalization; ii) Prehabilitation for major surgery; and, iii) Community-based interventions for frail elderly chronic patients. All three services have demonstrated efficacy and potential for health value generation. They reflect different implementation maturity levels. While full coverage of the entire urban health district of Barcelona-Esquerra (520 k inhabitants) is the main aim of home hospitalization, demonstration of sustainability at Hospital Clinic of Barcelona constitutes the core goal of the prehabilitation service. Likewise, full coverage of integrated care services addressed to frail chronic patients is aimed at the city of Badalona (216 k inhabitants). METHODS: The population-based analysis, as well as the three service-based protocols, follow observational and experimental study designs using a non-randomized intervention group (integrated care) compared with a control group (usual care) with a propensity score matching method. Evaluation of cost-effectiveness of the interventions using a Quadruple aim approach is a central outcome in all protocols. Moreover, multi-criteria decision analysis is explored as an innovative method for health delivery assessment. The following additional dimensions will also be addressed: i) Determinants of sustainability and scalability of the services; ii) Assessment of the technological support; iii) Enhanced health risk assessment; and, iv) Factors modulating service transferability. DISCUSSION: The current study offers a unique opportunity to undertake a comprehensive assessment of integrated care fostering deployment of services at regional level. The study outcomes will contribute refining service workflows, improving health risk assessment and generating recommendations for service selection. TRIALS REGISTRATION: NCT03130283 (date released 04/06/2018), NCT03768050 (date released 12/05/2018), NCT03767387 (date released 12/05/2018).

Planning, implementation and operation of a personalized patient management system for subjects with first suspect of cancer (OnkoNetwork): system description based on a qualitative study.

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.

What Is the Potential of Tissue-Engineered Pulmonary Valves in Children?

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.

Bioprosthetic aortic valve replacement in elderly patients: Meta-analysis and microsimulation.

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).

Beyond the clinical impact of aortic and pulmonary valve implantation: health-related quality of life, informal care and productivity†.

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.

Towards incentivising integration: A typology of payments for integrated care.

Traditional provider payment mechanisms may not create appropriate incentives for integrating care. Alternative payment mechanisms, such as bundled payments, have been introduced without uniform definitions, and existing payment typologies are not suitable for describing them. We use a systematic review combined with example integrated care programmes identified from practice in the Horizon2020 SELFIE project to inform a new typology of payment mechanisms for integrated care. The typology describes payments in terms of the scope of payment (Target population, Time, Sectors), the participation of providers (Provider coverage, Financial pooling/sharing), and the single provider/patient involvement (Income, Multiple disease/needs focus, and Quality measurement). There is a gap between rhetoric on the need for new payment mechanisms and those implemented in practice. Current payments for integrated care are mostly sector- and disease-specific, with questionable impact on those with the most need for integrated care. The typology provides a basis to improve financial incentives supporting more effective and efficient integrated care systems.

Cost Effectiveness of the Angiotensin Receptor Neprilysin Inhibitor Sacubitril/Valsartan for Patients with Chronic Heart Failure and Reduced Ejection Fraction in the Netherlands: A Country Adaptation Analysis Under the Former and Current Dutch Pharmacoeconomic Guidelines.

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.

Development of a Conceptual Model of Disease Progression for Use in Economic Modeling of Chronic Obstructive Pulmonary Disease.

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.

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.

Contemporary outcomes after surgical aortic valve replacement with bioprostheses and allografts: a systematic review and meta-analysis.

Many observational studies have reported outcomes after surgical aortic valve replacement (AVR), but there are no recent systematic reviews and meta-analyses including all available bioprostheses and allografts. The objective of this study is to provide a comprehensive and up-to-date overview of the outcomes after AVR with bioprostheses and allografts reported in the last 15 years. We conducted a systematic literature review (PROSPERO register: CRD42015017041) of studies published between 2000-15. Inclusion criteria were observational studies or randomized controlled trials reporting on outcomes of AVR with bioprostheses (stented or stentless) or allografts, with or without coronary artery bypass grafting (CABG) or valve repair procedure, with study population size n ≥ 30 and mean follow-up length ≥5 years. Fifty-four bioprosthesis studies and 14 allograft studies were included, encompassing 55 712 and 3872 patients and 349 840 and 32 419 patient-years, respectively. We pooled early mortality risk and linearized occurrence rates of valve-related events, reintervention and late mortality in a random-effects model. Sensitivity, meta-regression and subgroup analyses were performed to investigate the influence of outliers on the pooled estimates and to explore sources of heterogeneity. Funnel plots were used to investigate publication bias. Pooled early mortality risks for bioprostheses and allografts were 4.99% (95% confidence interval [CI], 4.44-5.62) and 5.03% (95% CI, 3.61-7.01), respectively. The late mortality rate was 5.70%/patient-year (95% CI, 4.99-5.62) for bioprostheses and 1.68%/patient-year (95% CI, 1.23-2.28) for allografts. Pooled reintervention rates for bioprostheses and allografts were 0.75%/patient-year (95% CI, 0.61-0.91) and 1.87%/patient-year (95% CI, 1.52-2.31), respectively. There was substantial heterogeneity in most outcomes. Meta-regression analyses identified covariates that could explain the heterogeneity: implantation period, valve type, patient age, gender, pre-intervention New York Heart Association class III/IV, concomitant CABG, study design and follow-up length. There is possible publication bias in all outcomes. This comprehensive systematic review and meta-analysis provides an overview of the outcomes after AVR with bioprostheses and allografts reported during the last 15 years. The results of this study can support patients and doctors in the prosthetic valve choice and can be used in microsimulation models to predict patient outcomes and estimate the cost-effectiveness of AVR with bioprostheses or allografts compared with current and future heart valve prostheses.