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Abstract Background This systematic review aims to describe the relation between physical inactivity and healthcare costs, by taking into account healthcare costs of physical-inactivity-related diseases (common practice), including physical-activity-related injuries (new) and costs in life-years gained due to avoiding diseases (new), whenever available. Moreover, the association between physical inactivity and healthcare costs may both be negatively and positively impacted by increased physical activity. Methods A systematic review was conducted, including records reporting on physical (in)activity in relation to healthcare costs for a general population. Studies were required to report sufficient information to calculate the percentage of total healthcare costs potentially attributable to physical inactivity. Results Of the 264 records identified, 25 were included in this review. Included studies showed substantial variation in the assessment methods of physical activity and in type of costs included. Overall, studies showed that physical inactivity is related to higher healthcare costs. Only one study included costs of healthcare resources used in prolonged life when physical-inactivity-related diseases were averted, showing net higher healthcare costs. No study included healthcare costs for physical-activity-related injuries. Conclusions Physical inactivity is associated with higher healthcare costs in the general population in the short-term. However, in the long-term aversion of diseases related with physical inactivity may increase longevity and, as a consequence, healthcare costs in life-years gained. Future studies should use a broad definition of costs, including costs in life-years gained and costs related to physical-activity-related injuries.

Objectives Increasing the price of tobacco is one of the most effective measures to reduce the prevalence of smoking. In the Netherlands, the excise tax on tobacco increased by €1.14 in 2020, raising the price of a standard package of cigarettes to €8.00. This study investigates how young adults intend to change their smoking behaviour in the case of hypothetical price increases of a pack of cigarettes, and which background characteristics are associated with intended behaviour change.Design A cross-sectional online survey was carried out between September and November 2020. Smokers indicated how they would react to several hypothetical increases in price. Four behavioural options were investigated: smoking less, quitting smoking, switching to another/cheaper product and buying cheaper cigarettes cross-border.Participants Data were obtained from 776 Dutch smokers between 15 and 25 years.Results At a hypothetical price of €10 per package, most respondents reported an intention to smoke less (67%), followed by switching to another/cheaper product (61%), quitting smoking (49%) and shopping for cigarettes cross-border (47%). Prior quit attempts, agreeing with the increase in excise tax and the intention to quit smoking in the future increased the odds of changing behaviour. Higher self-efficacy decreased the odds of behavioural change.Conclusion Many young adults intend to change their smoking behaviour in the event of increased prices. Although intended behaviour can deviate significantly from actual behaviour, an increase in excise tax may result in a significant amount of quit attempts and reduced smoking among young adults.

Abstract Background Many patients with metastatic breast cancer experience cancer- and treatment-related side effects that impair activities of daily living and negatively affect the quality of life. There is a need for interventions that improve quality of life by alleviating fatigue and other side effects during palliative cancer treatment. Beneficial effects of exercise have been observed in the curative setting, but, to date, comparable evidence in patients with metastatic breast cancer is lacking. The aim of this study is to assess the effects of a structured and individualized 9-month exercise intervention in patients with metastatic breast cancer on quality of life, fatigue, and other cancer- and treatment-related side effects. Methods The EFFECT study is a multinational, randomized controlled trial including 350 patients with metastatic breast cancer. Participants are randomly allocated (1:1) to an exercise or control group. The exercise group participates in a 9-month multimodal exercise program, starting with a 6-month period where participants exercise twice a week under the supervision of an exercise professional. After completing this 6-month period, one supervised session is replaced by one unsupervised session for 3 months. In addition, participants are instructed to be physically active for ≥30 min/day on all remaining days of the week, while being supported by an activity tracker and exercise app. Participants allocated to the control group receive standard medical care, general written physical activity advice, and an activity tracker, but no structured exercise program. The primary outcomes are quality of life (EORTC QLQ-C30, summary score) and fatigue (EORTC QLQ-FA12), assessed at baseline, 3, 6 (primary endpoint), and 9 months post-baseline. Secondary outcomes include physical fitness, physical performance, physical activity, anxiety, depression, pain, sleep problems, anthropometric data, body composition, and blood markers. Exploratory outcomes include quality of working life, muscle thickness, urinary incontinence, disease progression, and survival. Additionally, the cost-effectiveness of the exercise program is assessed. Adherence and safety are monitored throughout the intervention period. Discussion This large randomized controlled trial will provide evidence regarding the (cost-) effectiveness of exercise during treatment of metastatic breast cancer. If proven (cost-)effective, exercise should be offered to patients with metastatic breast cancer as part of standard care. Trial registration ClinicalTrials.gov NCT04120298 . Registered on October 9, 2019.

BackgroundIn the treatment of Non-Small Cell Lung Cancer (NSCLC) the combination of Immuno- Oncotherapy (IO) and chemotherapy (CT) has been found to be superior to IO or CT alone for patients’ survival. Patients and clinicians are confronted with a preference sensitive choice between a more aggressive treatment with a greater negative effect on quality of life versus alternatives that are less effective but have fewer side effects.ObjectivesThe aims of this study were to: (a) quantify patients’ preferences for relevant attributes related to Immuno-Oncotherapy treatment alternatives, and (b) evaluate the maximum acceptable risk (MAR)/Minimum acceptable benefit (MAB) that patients would accept for treatment alternatives.MethodsAn online preference survey using discrete-choice experiment (DCE) was completed by NSCLC patients from two hospitals in Italy and Belgium. The survey asked patients’ preferences for five patient- relevant treatment attributes. The DCE was developed using a Bayesian D-efficient design. DCE analyses were performed using mixed logit models. Information regarding patient demographics, health literacy, locus of control, and quality of life was also collected.Results307 patients (158 Italian, 149 Belgian), stage I to IV, completed the survey. Patients preferred treatments with a higher 5-year survival chance as the most important attribute over all the other attributes. Preference heterogeneity for the attribute weights depended on health literacy, patients’ age and locus of control. Patients were willing to accept a substantially increased risks of developing side effects in exchange for the slightest increase (1%) in the chance of surviving at least 5 years from the diagnosis of cancer. Similarly, patients were willing to accept a switch in the mode of administration or complete loss of hair to obtain an increase in survival.ConclusionIn this study, the proportion of respondents who systematically preferred survival over all other treatment attributes was particularly high. Age, objective health literacy and locus of control accounted for heterogeneity in patients’ preferences. Evidence on how NSCLC patients trade between survival and other NSCLC attributes can support regulators and other stakeholders on assessing clinical trial evidence and protocols, based on patients’ conditions and socio-demographic parameters.

Abstract Background Neonates with critical congenital heart disease (CCHD) undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk of brain injury that may result in adverse neurodevelopment. To date, no therapy is available to improve long-term neurodevelopmental outcomes of CCHD neonates. Allopurinol, a xanthine oxidase inhibitor, prevents the formation of reactive oxygen and nitrogen species, thereby limiting cell damage during reperfusion and reoxygenation to the brain and heart. Animal and neonatal studies suggest that allopurinol reduces hypoxic-ischemic brain injury and is cardioprotective and safe. This trial aims to test the hypothesis that allopurinol administration in CCHD neonates will result in a 20% reduction in moderate to severe ischemic and hemorrhagic brain injury. Methods This is a phase III, randomized, quadruple-blinded, placebo-controlled, multicenter trial. Neonates with a prenatal or postnatal CCHD diagnosis requiring cardiac surgery with CPB in the first 4 weeks after birth are eligible to participate. Allopurinol or mannitol-placebo will be administered intravenously in 2 doses early postnatally in neonates diagnosed antenatally and 3 doses perioperatively of 20 mg/kg each in all neonates. The primary outcome is a composite endpoint of moderate/severe ischemic or hemorrhagic brain injury on early postoperative MRI, being too unstable for postoperative MRI, or mortality within 1 month following CPB. A total of 236 patients (n = 188 with prenatal diagnosis) is required to demonstrate a reduction of the primary outcome incidence by 20% in the prenatal group and by 9% in the postnatal group (power 80%; overall type 1 error controlled at 5%, two-sided), including 1 interim analysis at n = 118 (n = 94 with prenatal diagnosis) with the option to stop early for efficacy. Secondary outcomes include preoperative and postoperative brain injury severity, white matter injury volume (MRI), and cardiac function (echocardiography); postnatal and postoperative seizure activity (aEEG) and regional cerebral oxygen saturation (NIRS); neurodevelopment at 3 months (general movements); motor, cognitive, and language development and quality of life at 24 months; and safety and cost-effectiveness of allopurinol. Discussion This trial will investigate whether allopurinol administered directly after birth and around cardiac surgery reduces moderate/severe ischemic and hemorrhagic brain injury and improves cardiac function and neurodevelopmental outcome in CCHD neonates. Trial registration EudraCT 2017-004596-31. Registered on November 14, 2017. ClinicalTrials.gov NCT04217421. Registered on January 3, 2020

Introduction Ear pain is the most prominent symptom of childhood acute otitis media (AOM). To control the pain and reduce reliance on antibiotics, evidence of effectiveness for alternative interventions is urgently needed. This trial aims to investigate whether analgesic ear drops added to usual care provide superior ear pain relief over usual care alone in children presenting to primary care with AOM.Methods and analysis This is a pragmatic, two-arm, individually randomised, open, superiority trial with cost-effectiveness analysis and nested mixed-methods process evaluation in general practices in the Netherlands. We aim to recruit 300 children aged 1–6 years with a general practitioner (GP) diagnosis of AOM and ear pain. Children will be randomly allocated (ratio 1:1) to either (1) lidocaine hydrochloride 5 mg/g ear drops (Otalgan) one to two drops up to six times daily for a maximum of 7 days in addition to usual care (oral analgesics, with/without antibiotics); or (2) usual care. Parents will complete a symptom diary for 4 weeks as well as generic and disease-specific quality of life questionnaires at baseline and 4 weeks. The primary outcome is the parent-reported ear pain score (0–10) over the first 3 days. Secondary outcomes include proportion of children consuming antibiotics, oral analgesic use and overall symptom burden in the first 7 days; number of days with ear pain, number of GP reconsultations and subsequent antibiotic prescribing, adverse events, complications of AOM and cost-effectiveness during 4-week follow-up; generic and disease-specific quality of life at 4 weeks; parents’ and GPs’ views and experiences with treatment acceptability, usability and satisfaction.Ethics and dissemination The Medical Research Ethics Committee Utrecht, the Netherlands, has approved the protocol (21-447/G-D). All parents/guardians of participants will provide written informed consent. Study results will be submitted for publication in peer-reviewed medical journals and presented at relevant (inter)national scientific meetings.Trial registration The Netherlands Trial Register: NL9500; date of registration: 28 May 2021. At the time of publication of the study protocol paper, we were unable to make any amendments to the trial registration record in the Netherlands Trial Register. The addition of a data sharing plan was required to adhere to the International Committee of Medical Journal Editors guidelines. The trial was therefore reregistered in ClinicalTrials.gov (NCT05651633; date of registration: 15 December 2022). This second registration is for modification purposes only and the Netherlands Trial Register record (NL9500) should be regarded as the primary trial registration.

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.

Abstract Background Healthcare costs related to ESRD are well-described, but broader societal costs of ESRD are less known. This study aimed to estimate patient and family costs, including informal care costs and out-of-pocket costs, and costs due to productivity loss related to ESRD, for patients receiving dialysis and living with a kidney transplant, using a bottom-up approach. Methods A total of 655 patients were asked to complete a digital questionnaire consisting of two standardised instruments (iMCQ and iPCQ) from November 2016 through January 2017. We applied a retrospective bottom-up cost estimation by combining data from the questionnaire with unit prices from the Dutch costing manual. Results Our study sample consisted of 230 patients, of which 165 were kidney transplant recipients and 65 received dialysis. The total annual non-healthcare related costs were estimated at €8284 (SD: €14,266) for transplant recipients and €23,488 (SD: €39,434) for dialysis patients. Costs due to productivity loss contributed most to the total non-healthcare costs (66% for transplant recipients and 65% for dialysis patients), followed by informal care costs (26% resp. 29%) and out-of-pocket costs, such as medication and travel expenses (8% resp. 6%). Conclusion By exposing patient, family and productivity costs, our study revealed that dialysis and transplantation are not only costly within the healthcare system, but also incur high non-healthcare costs (18–23% resp. 35% of the total societal costs). It is important to reveal these types of non-healthcare costs in order to understand the full burden of ESRD for society and the potential impact of new therapies.

Abstract Background Recent attempts of active disinvestment (i.e. withdrawal of reimbursement by means of a policy decision) of reimbursed healthcare interventions in the Netherlands have differed in their outcome: some attempts were successful, with interventions actually being disinvested. Other attempts were terminated at some point, implying unsuccessful disinvestment. This study aimed to obtain insight into recent active disinvestment processes, and to explore what aspects affect their outcome. Methods Semi-structured interviews were conducted from January to December 2018 with stakeholders (e.g. patients, policymakers, physicians) who were involved in the policy process of five cases for which the full or partial withdrawal of reimbursement was considered in the Netherlands between 2007 and 2017: benzodiazepines, medication for Fabry disease, quit smoking programme, psychoanalytic therapy and maternity care assistance. These cases covered both interventions that were eventually disinvested and interventions for which reimbursement was maintained after consideration. Interviews were transcribed verbatim, double coded and analyzed using thematic analysis. Results The 37 interviews showed that support for disinvestment from stakeholders, especially from healthcare providers and policymakers, strongly affected the outcome of the disinvestment process. Furthermore, the institutional role of stakeholders as legitimized by the Dutch health insurance system, their financial interests in maintaining or discontinuing reimbursement, and the possibility to relieve the consequences of disinvestment for current patients affected the outcome of the disinvestment process as well. A poor organization of patient groups may make it difficult for patients to exert pressure, which may contribute to successful disinvestment. No evidence was found of a consistent role of the formal Dutch package criteria (i.e. effectiveness, cost-effectiveness, necessity and feasibility) in active disinvestment processes. Conclusions Contextual factors as well as the possibility to relieve the consequences of disinvestment for current patients are important determinants of the outcome of active disinvestment processes. These results provide insight into active disinvestment processes and their determinants, and provide guidance to policymakers for a potentially more successful approach for future active disinvestment processes.

Abstract Background Acute otitis media (AOM) is among the most common paediatric conditions managed in primary care. Most recent estimates of the cost of AOM date from a decade ago and lack a full societal perspective. We therefore explored the societal cost of childhood AOM in the Netherlands within the setting of a trial comparing the effectiveness of an intervention aimed at educating general practitioners (GPs) about pain management in AOM compared to usual care. Methods Economic analysis alongside a cluster randomised controlled trial conducted between February 2015 and May 2018 in 37 practices (94 GPs). In total, 224 children with AOM were included of which 223 (99%) completed the trial (intervention: n = 94; control: n = 129). The cost of AOM due to health care costs, patient and family costs, and productivity losses by parent caregivers were retrieved from study diaries and primary care electronic health records, during 28-day follow-up. We calculated mean cost (€ and $) per AOM episode per patient with standard deviations (SD, in €) regardless of study group assignment because there was no clinical effect of the trial intervention. In sensitivity analysis, we calculated cost in the intervention and usual care group, after exclusion of extreme outliers. Results Mean total AOM cost per patient were €565.93 or $638.78 (SD €1071.01); nearly 90% of these costs were due to productivity losses experienced by parents. After exclusion of outliers, AOM cost was €526.70 or $594.50 (SD €987.96) and similar in the intervention and usual care groups: €516.10 or $582.53 (SD €949.69) and €534.55 or $603.36 (SD €920.55) respectively. Conclusions At €566 or $639 per episode, societal cost of AOM is higher than previously known and mainly driven by productivity losses by children’s parents. Considering its high incidence, AOM poses a significant economic burden that extends beyond direct medical costs. Trial registration Netherlands Trial Register no. NTR4920: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4920 .

Abstract Background Cardiometabolic diseases (CMD) are the major cause of death worldwide and are associated with a lower quality of life and high healthcare costs. To prevent a further rise in CMD and related healthcare costs, early detection and adequate management of individuals at risk could be an effective preventive strategy. The objective of this study was to determine long-term cost-effectiveness of stepwise CMD risk assessment followed by individualized treatment if indicated compared to care as usual. A computer-based simulation model was used to project long-term health benefits and cost-effectiveness, assuming the prevention program was implemented in Dutch primary care. Methods A randomized controlled trial in a primary care setting in which 1934 participants aged 45–70 years without recorded CMD or CMD risk factors participated. The intervention group was invited for stepwise CMD risk assessment through a risk score (step 1), additional risk assessment at the practice in case of increased risk (step 2) and individualized follow-up treatment if indicated (step 3). The control group was not invited for risk assessment, but completed a health questionnaire. Results of the effectiveness analysis on systolic blood pressure (− 2.26 mmHg; 95% CI − 4.01: − 0.51) and total cholesterol (− 0.15 mmol/l; 95% CI − 0.23: − 0.07) were used in this analysis. Outcome measures were the costs and benefits after 1-year follow-up and long-term (60 years) cost-effectiveness of stepwise CMD risk assessment compared to no assessment. A computer-based simulation model was used that included data on disability weights associated with age and disease outcomes related to CMD. Analyses were performed taking a healthcare perspective. Results After 1 year, the average costs in the intervention group were 260 Euro higher than in the control group and differences were mainly driven by healthcare costs. No meaningful change was found in EQ 5D-based quality of life between the intervention and control groups after 1-year follow-up (− 0.0154; 95% CI − 0.029: 0.004). After 60 years, cumulative costs of the intervention were 41.4 million Euro and 135 quality-adjusted life years (QALY) were gained. Despite improvements in blood pressure and cholesterol, the intervention was not cost-effective (ICER of 306,000 Euro/QALY after 60 years). Scenario analyses did not allow for a change in conclusions with regard to cost-effectiveness of the intervention. Conclusions Implementation of this primary care-based CMD prevention program is not cost-effective in the long term. Implementation of this program in primary care cannot be recommended. Trial registration Dutch Trial Register NTR4277 , registered on 26 November 2013

Abstract Background To optimize the focus of future public information campaigns in The Netherlands promoting the uptake of vaccines among adults and children, we quantified the contribution of several attributes to the vaccination decision. Method We performed a discrete choice experiment (DCE) among Dutch adults including six attributes, i.e. vaccine effectiveness, vaccine-preventable burden of disease (specified in severity and frequency), accessibility of vaccination in terms of co-payment and prescription requirements, frequency of mild side-effects, population-level vaccination coverage and local vaccination coverage among family and friends. Participants answered the DCE from their own perspective (‘oneself’ group) or with regard to a vaccine decision for their youngest child (‘child’ group). The data was analysed by means of panel mixed logit models. Results We included 1547 adult participants (825 ‘oneself’ and 722 ‘child’). Vaccine effectiveness was the most important attribute in the ‘oneself’ group, followed by burden of disease (relative importance (RI) 78%) and accessibility (RI 76%). In the ‘child’ group, burden of disease was most important, but tied closely with vaccine effectiveness (RI 97%). Of less importance was the risk of mild vaccine-related side-effects and both population and local vaccination coverage. Interestingly, participants were more willing to vaccinate when uptake among the population or family and friends was high, indicating that social influence and social norms plays a role. Conclusions Vaccine effectiveness and disease severity are key attributes in vaccination decision-making for adults making a decision for themselves and for parents who decide for their children. Hence, public information campaigns for both adult and child vaccination should primarily focus on these two attributes. In addition, reinforcing social norms may be considered.

Abstract Background Traumatic brain injury (TBI) is the main cause of mortality and severe morbidity in cyclists admitted to Dutch emergency departments (EDs). Although the use of bicycle helmets is an effective way of preventing TBI, this is uncommon in the Netherlands. An option to increase its use is through a legal enforcement. However, little is known about the cost-effectiveness of such mandatory use of helmets in the Dutch context. The current study aimed to assess the cost-effectiveness of a law that enforces helmet use to reduce TBI and TBI-related mortality. Methods The cost-effectiveness was estimated through decision tree modelling. In this study, wearing bicycle helmets enforced by law was compared with the current situation of infrequent voluntary helmet use. The total Dutch cycling population, consisting of 13.5 million people, was included in the model. Model data and parameters were obtained from Statistics Netherlands, the National Road Traffic Database, Dutch Injury Surveillance System, and literature. Effects included were numbers of TBI, death, and disability-adjusted life years (DALY). Costs included were healthcare costs, costs of productivity losses, and helmet costs. Sensitivity analysis was performed to assess which parameter had the largest influence on the incremental cost-effectiveness ratio (ICER). Results The intervention would lead to an estimated reduction of 2942 cases of TBI and 46 deaths. Overall, the incremental costs per 1) death averted, 2) per TBI averted, and 3) per DALY averted were estimated at 1) € 2,002,766, 2) € 31,028 and 3) € 28,465, respectively. Most favorable were the incremental costs per DALY in the 65+ age group: € 17,775. Conclusions The overall costs per DALY averted surpassed the Dutch willingness to pay threshold value of € 20,000 for cost-effectiveness of preventive interventions. However, the cost per DALY averted for the elderly was below this threshold, indicating that in this age group largest effects can be reached. If the price of a helmet would reduce by 20%, which is non-hypothetical in a situation of large-scale purchases and use of these helmets, the introduction of this regulation would result in an intervention that is almost cost-effective in all age groups.

Abstract Background Although evidence is accumulating that lifestyle modification may be cost-effective in patients with prediabetes, information is limited on the cost-effectiveness of interventions implemented in public health and primary health care settings. Evidence from well-conducted pragmatic trials is needed to gain insight into the realistic cost-effectiveness of diabetes prevention interventions in real-world settings. The aim of this study is to assess the cost-effectiveness of the SLIMMER lifestyle intervention targeted at patients at high risk of developing type 2 diabetes compared with usual health care in a primary care setting in the Netherlands. Methods Three hundred and sixteen high-risk subjects were randomly assigned to the SLIMMER lifestyle intervention or to usual health care. Costs and outcome assessments were performed at the end of the intervention (12 months) and six months thereafter (18 months). Costs were assessed from a societal perspective. Patients completed questionnaires to assess health care utilisation, participant out-of-pocket costs, and productivity losses. Quality Adjusted Life Years (QALY) were calculated based on the SF-36 questionnaire. Cost-effectiveness planes and acceptability curves were generated using bootstrap analyses. Results The cost-effectiveness analysis showed that the incremental costs of the SLIMMER lifestyle intervention were €547 and that the incremental effect was 0.02 QALY, resulting in an incremental cost-effectiveness ratio (ICER) of €28,094/QALY. When cost-effectiveness was calculated from a health care perspective, the ICER decreased to €13,605/QALY, with a moderate probability of being cost-effective (56% at a willingness to pay, WTP, of €20,000/QALY and 81% at a WTP of €80,000/QALY). Conclusions The SLIMMER lifestyle intervention to prevent type 2 diabetes had a low to moderate probability of being cost-effective, depending on the perspective taken. Trial registration The SLIMMER study is retrospectively registered with ClinicalTrials.gov (Identifier NCT02094911) since March 19, 2014.

Introduction: Lung cancer is the deadliest and most prevalent cancer worldwide. Lung cancer treatments have different characteristics and are associated with a range of benefits and side effects for patients. Such differences may raise uncertainty among drug developers, regulators, payers, and clinicians regarding the value of these treatment effects to patients. The value of conducting patient preference studies (using qualitative and/or quantitative methods) for benefits and side effects of different treatment options has been recognized by healthcare stakeholders, such as drug developers, regulators, health technology assessment bodies, and clinicians. However, evidence-based guidelines on how and when to conduct and use these studies in drug decision-making are lacking. As part of the Innovative Medicines Initiative PREFER project, we developed a protocol for a qualitative study that aims to understand which treatment characteristics are most important to lung cancer patients and to develop attributes and levels for inclusion in a subsequent quantitative preference survey.Methods: The study protocol specifies a four-phased approach: (i) a scoping literature review of published literature, (ii) four focus group discussions with stage III and IV Non-Small Cell Lung Cancer patients, (iii) two nominal group discussions with stage III and IV Non-Small Cell Lung Cancer patients, and (iv) multi-stakeholder discussions involving clinicians and preference experts.Discussion: This protocol outlines methodological and practical steps as to how qualitative research can be applied to identify and develop attributes and levels for inclusion in patient preference studies aiming to inform decisions across the drug life cycle. The results of this study are intended to inform a subsequent quantitative preference survey that assesses patient trade-offs regarding lung cancer treatment options. This protocol may assist researchers, drug developers, and decision-makers in designing qualitative studies to understand which treatment aspects are most valued by patients in drug development, regulation, and reimbursement.

Introduction End-stage kidney disease (ESKD) is a major public health problem affecting more than 2 million people worldwide. It is one of the most severe chronic non-communicable diseases. Haemodialysis (HD) is the most common therapeutic option but is also associated with a risk of cardiovascular events, hospitalisation and suboptimal quality of life. Over the past decades, haemodiafiltration (HDF) has become available. Although high-dose HDF has shown some promising survival advantage compared to conventional HD, the evidence remains controversial. A Cochrane systematic review found, in low-quality trials, with various convective forms of dialysis, a reduction in cardiovascular, but not all-cause mortality and the effects on non-fatal cardiovascular events and hospitalisation were uncertain. In contrast, an individual patient data analysis suggested that high-dose HDF reduced both all-cause and cardiovascular mortality compared to HD. In view of these discrepant results, a definitive trial is required to determine whether high-dose HDF is preferable to high-flux HD. The comparison of high-dose HDF with high-flux HD (CONVINCE) study will assess the benefits and harms of high-dose HDF versus a conventional high-flux HD in adults with ESKD.Methods and analysis This international, prospective, open label, randomised controlled trial aims to recruit 1800 ESKD adults treated with HD in nine European countries. Patients will be randomised 1:1 to high-dose HDF versus continuation of conventional high-flux HD. The primary outcome will be all-cause mortality at 3 years’ follow-up. Secondary outcomes will include cause-specific mortality, cardiovascular events, all-cause and infection-related hospitalisations, patient-reported outcomes (eg, health-related quality of life) and cost-effectiveness.Ethics and dissemination The CONVINCE study will address the question of benefits and harms of high-dose HDF compared to high-flux HD for kidney replacement therapy in patients with ESKD with a focus on survival, patient perspectives and cost-effectiveness.Trial registration number Netherlands National Trial Register (NTR 7138).

Abstract Background Whilst current guidelines highlight the importance of pain management for children with acute otitis media (AOM), there is evidence to suggest that this is not implemented in everyday practice. We have developed a primary care-based multifaceted educational intervention to optimise pain management in children with AOM, and we trial its clinical and cost effectiveness. Methods This cluster randomised controlled trial aims to recruit 250 children aged 6 months to 10 years presenting with AOM to general practitioners (GPs) in 30 primary care centres (PCCs) across the Netherlands. GPs in the PCCs allocated to the intervention group receive a blended GP educational programme (online and face-to-face training). The intervention asks GPs to proactively discuss pain management with parents using an information leaflet, and to prescribe paracetamol and ibuprofen according to current guidelines. GPs in both groups complete an online module illustrating various otoscopic images to standardise AOM diagnosis. GPs in the PCCs allocated to the control group do not receive any further training and provide ‘care as usual’. During the 4-week follow-up, parents complete a symptom diary. The primary outcome is the difference in parent-reported mean earache scores over the first 3 days. Secondary outcomes include both number of days with earache and fever, GP re-consultations for AOM, antibiotic prescriptions, and costs. Analysis will be by intention-to-treat. Discussion The optimal use of analgesics through the multifaceted intervention may provide symptom relief and thereby reduce re-consultations and antibiotic prescriptions in children with AOM. Trial registration Netherlands Trial Register, NTR4920. Registered on 19 December 2014.

Introduction: Many economic evaluations of HPV vaccination have been published, but most have focused on the prevention of cervical disease as a primary health outcome. The cost-effectiveness of vaccination is likely to be underestimated if not all HPV-associated diseases are taken into account. In this review, we assess the influence of non-cervical HPV-associated diseases on the incremental cost-effectiveness ratio (ICER) of preadolescent HPV vaccination. Areas covered: We systematically searched the literature and identified 18 studies that included non-cervical diseases in the estimates of cost-effectiveness of HPV-vaccination. When taking other HPV-related diseases into account compared to not including such other diseases, the mean ICERs were 2.85 times more favorable for girls only vaccination and 3.89 times for gender neutral vaccination. Expert commentary: Including non-cervical diseases in economic evaluations of HPV vaccination programs makes it more likely that the ICER falls beneath accepted cost-effectiveness thresholds and therefore increases the scope for gender neutral vaccination.

In the Netherlands, toxoplasmosis ranks second in disease burden among foodborne pathogens with an estimated health loss of 1,900 Disability Adjusted Life Years and a cost-of-illness estimated at €45 million annually. Therefore, effective and preferably cost-effective preventive interventions are warranted. Freezing meat intended for raw or undercooked consumption and improving biosecurity in pig farms are promising interventions to prevent Toxoplasma gondii infections in humans. Putting these interventions into practice would expectedly reduce the number of infections; however, the net benefits for society are unknown. Stakeholders bearing the costs for these interventions will not necessary coincide with the ones having the benefits. We performed a Social Cost-Benefit Analysis to evaluate the net value of two potential interventions for the Dutch society. We assessed the costs and benefits of the two interventions and compared them with the current practice of education, especially during pregnancy. A 'minimum scenario' and a 'maximum scenario' was assumed, using input parameters with least benefits to society and input parameters with most benefits to society, respectively. For both interventions, we performed different scenario analyses. The freezing meat intervention was far more effective than the biosecurity intervention. Despite high freezing costs, freezing two meat products: steak tartare and mutton leg yielded net social benefits in both the minimum and maximum scenario, ranging from €10.6 million to €31 million for steak tartare and €0.6 million to €1.5 million for mutton leg. The biosecurity intervention would result in net costs in all scenarios ranging from €1 million to €2.5 million, due to high intervention costs and limited benefits. From a public health perspective (i.e. reducing the burden of toxoplasmosis) and the societal perspective (i.e. a net benefit for the Dutch society) freezing steak tartare and leg of mutton is to be considered.

BackgroundThe aim of this study is to present average annual healthcare costs for Dutch renal replacement therapy (RRT) patients for 7 treatment modalities.MethodsHealth insurance claims data from 2012-2014 were used. All patients with a 2014 claim for dialysis or kidney transplantation were selected. The RRT related and RRT unrelated average annual healthcare costs were analysed for 5 dialysis modalities (in-centre haemodialysis (CHD), home haemodialysis (HHD), continuous ambulatory peritoneal dialysis (CAPD), automated peritoneal dialysis (APD) and multiple dialysis modalities in a year (Mix group)) and 2 transplant modalities (kidney from living and deceased donor, respectively).ResultsThe total average annual healthcare costs in 2014 ranged from €77,566 (SD = €27,237) for CAPD patients to €105,833 (SD = €30,239) for patients in the Mix group. For all dialysis modalities, the vast majority (72-84%) of costs was RRT related. Patients on haemodialysis ≥4x/week had significantly higher average annual costs compared to those dialyzing 3x/week (Δ€19,122). Costs for kidney transplant recipients were €85,127 (SD = €39,679) in the year of transplantation and rapidly declined in the first and second year after successful transplantation (resp. €29,612 (SD = €34,099) and €15,018 (SD = €16,186)). Transplantation with a deceased donor kidney resulted in higher costs (€99,450, SD = €36,036)) in the year of transplantation compared to a living donor kidney transplantation (€73,376, SD = €38,666).ConclusionsCAPD patients have the lowest costs compared to other dialysis modalities. Costs in the year of transplantation are 25% lower for patients with kidneys from living vs. deceased donor. After successful transplantation, annual costs decline substantially to a level that is approximately 14-19% of annual dialysis costs.

Abstract Background To be able to make valid inferences on stated preference data from a Discrete Choice Experiment (DCE) it is essential that researchers know if participants were actively involved, understood and interpreted the provided information correctly and whether they used complex decision strategies to make their choices and thereby acted in accordance with the continuity axiom. Methods During structured interviews, we explored how 70 participants evaluated and completed four discrete choice tasks aloud. Hereafter, additional questions were asked to further explore if participants understood the information that was provided to them and whether they used complex decision strategies (continuity axiom) when making their choices. Two existing DCE questionnaires on rotavirus vaccination and prostate cancer-screening served as case studies. Results A large proportion of the participants was not able to repeat the exact definition of the risk attributes as explained to them in the introduction of the questionnaire. The majority of the participants preferred more optimal over less optimal risk attribute levels. Most participants (66 %) mentioned three or more attributes when motivating their decisions, thereby acting in accordance with the continuity axiom. However, 16 out of 70 participants continuously mentioned less than three attributes when motivating their decision. Lower educated and less literate participants tended to mention less than three attributes when motivating their decision and used trading off between attributes less often as a decision-making strategy. Conclusion The majority of the participants seemed to have understood the provided information about the choice tasks, the attributes, and the levels. They used complex decision strategies (continuity axiom) and are therefore capable to adequately complete a DCE. However, based on the participants’ age, educational level and health literacy additional, actions should be undertaken to ensure that participants understand the choice tasks and complete the DCE as presumed.

BACKGROUND:Chronic infection with hepatitis B or C virus (HBV/HCV) can progress to cirrhosis, liver cancer, and even death. In a low endemic country as the Netherlands, migrants are a key risk group and could benefit from early diagnosis and antiviral treatment. We assessed the cost-effectiveness of screening foreign-born migrants for chronic HBV and/or HCV using a societal perspective. METHODS:The cost-effectiveness was evaluated using a Markov model. Estimates on prevalence, screening programme costs, participation and treatment uptake, transition probabilities, healthcare costs, productivity losses and utilities were derived from the literature. The cost per Quality Adjusted Life Year (QALY) gained was estimated and sensitivity analyses were performed. RESULTS:For most migrant groups with an expected high number of chronically infected cases in the Netherlands combined screening is cost-effective, with incremental cost-effectiveness ratios (ICERs) ranging from €4,962/QALY gained for migrants originating from the Former Soviet Union and Vietnam to €9,375/QALY gained for Polish migrants. HBV and HCV screening proved to be cost-effective for migrants from countries with chronic HBV or HCV prevalence of ≥0.41% and ≥0.22%, with ICERs below the Dutch cost-effectiveness reference value of €20,000/QALY gained. Sensitivity analysis showed that treatment costs influenced the ICER for both infections. CONCLUSIONS:For most migrant populations in a low-endemic country offering combined HBV and HCV screening is cost-effective. Implementation of targeted HBV and HCV screening programmes to increase early diagnosis and treatment is important to reduce the burden of chronic hepatitis B and C among migrants.

BACKGROUND:A healthy diet is important for normal growth and development. Exposure to undernutrition during important developmental periods such as childhood and adolescence can have effects later in life. Inhabitants of the west of the Netherlands were exposed to severe undernutrition during the famine in the last winter of the second World War (1944-1945). OBJECTIVE:We investigated if exposure of women to the Dutch famine during childhood and adolescence was associated with an unhealthy lifestyle later in life. DESIGN:We studied 7,525 women from the Prospect-EPIC cohort, recruited in 1993-97 and aged 0-18 years during the Dutch famine. An individual famine score was calculated based on self-reported information about experience of hunger and weight loss. We investigated the association between famine exposure in early life and four lifestyle factors in adulthood: smoking, alcohol consumption, physical activity level and a Mediterranean-style diet. RESULTS:Of the 7,525 included women, 46% were unexposed, 38% moderately exposed and 16% severely exposed to the Dutch famine. Moderately and severely exposed women were more often former or current smokers compared to women that did not suffer from the famine: adjusted prevalence ratio 1.10 (95% CI: 1.05; 1.14) and 1.18 (1.12; 1.25), respectively. They also smoked more pack years than unexposed women. Severely exposed women were more often physically inactive than unexposed women, adjusted prevalence ratio 1.32 (1.06; 1.64). Results did not differ between exposure age categories (0-9 and 10-17 years). We found no associations of famine exposure with alcohol consumption and no dose-dependent relations with diet. CONCLUSIONS:Exposure to famine early in female life may be associated with higher prevalence of smoking and physical inactivity later in life, but not with unhealthy diet and alcohol consumption.

BACKGROUND:People who inject drugs (PWID) are disproportionally affected by the hepatitis C virus (HCV) infection. The efficacy of HCV treatment has significantly improved in recent years with the introduction of direct-acting antivirals (DAAs). However, DAAs are more costly than pegylated-interferon and ribavirin (PegIFN/RBV). We aimed to assess the cost-effectiveness of four HCV treatment strategies among PWID and treatment scale-up. METHODS:An individual-based model was used describing HIV and HCV transmission and disease progression among PWID. We considered two epidemiological situations. A declining epidemic, based on the situation in Amsterdam, the Netherlands, and a stable HCV epidemic, as observed in other settings. Data on HCV incidence, prevalence, treatment setting and uptake were derived from observed data among PWID in Amsterdam. We assessed the incremental cost-effectiveness ratio (ICER, costs in €/quality-adjusted life year (QALY)) of four treatment strategies: 1) PegIFN/RBV; 2) sofosbuvir/RBV for genotype 2-3 and dual DAA for genotype 1-4; 3) Dual DAA for all genotypes; 4) Dual DAA with 3x treatment uptake. RESULTS:In both types of epidemic, dual DAA therapy was most cost-effective strategy. In the declining epidemic, dual DAA yielded an ICER of 344 €/QALY while in the stable epidemic dual DAA led to cost-savings. Scaling-up treatment was also highly cost-effective. Our results were robust over a range of sensitivity analyses. CONCLUSION:HCV treatment with DAA-containing regimens is a highly cost-effective intervention among PWID. Based on the economic and population benefits of scaling-up treatment, stronger efforts are needed to achieve higher uptake rates among PWID.

The aim of our study was to relate four modifiable lifestyle factors (smoking status, body mass index, physical activity and diet) to health expectancy, using quality-adjusted life years (QALYs) in a prospective cohort study. Data of the prospective EPIC-NL study were used, including 33,066 healthy men and women aged 20-70 years at baseline (1993-7), followed until 31-12-2007 for occurrence of disease and death. Smoking status, body mass index, physical activity and adherence to a Mediterranean-style diet (excluding alcohol) were investigated separately and combined into a healthy lifestyle score, ranging from 0 to 4. QALYs were used as summary measure of healthy life expectancy, combining a person's life expectancy with a weight for quality of life when having a chronic disease. For lifestyle factors analyzed separately the number of years living longer in good health varied from 0.12 year to 0.84 year, after adjusting for covariates. A combination of the four lifestyle factors was positively associated with higher QALYs (P-trend

to determine to what extent the inclusion of an opt-out option in a DCE may have an effect on choice behaviour and therefore might influence the attribute level estimates, the relative importance of the attributes and calculated trade-offs.781 Dutch Type 2 Diabetes Mellitus patients completed a questionnaire containing nine choice tasks with an opt-out option and nice forced choice tasks. Mixed-logit models were used to estimate the relative importance of the five lifestyle program related attributes that were included. Willingness to pay (WTP) values were calculated and it was tested whether results differed between respondents who answered the choice tasks with an opt-out option in the first or second part of the questionnaire.21.4% of the respondents always opted out. Respondents who were given the opt-out option in the first part of the questionnaire as well as lower educated respondents significantly more often opted out. For both the forced and unforced choice model, different attributes showed significant estimates, the relative importance of the attributes was equal. However, due to differences in relative importance weights, the WTP values for the PA schedule differed significantly between both datasets.Results show differences in opting out based on the location of the opt-out option and respondents' educational level; this resulted in small differences between the forced and unforced choice model. Since respondents seem to learn from answering forced choice tasks, a dual response design might result in higher data quality compared to offering a direct opt-out option. Future research should empirically explore how choice sets should be presented to make them as easy and less complex as possible in order to reduce the proportion of respondents that opts-out due to choice task complexity. Moreover, future research should debrief respondents to examine the reasons for choosing the opt-out alternative.

Background: Dietary patterns have been associated with the incidence or mortality of individual non-communicable diseases, but their association with disease burden has received little attention. Objective: The aim of our study was to relate dietary patterns to health expectancy using quality-adjusted life years (QALYs) as outcome parameter. Methods: Data from the EPIC-NL study were used, a prospective cohort study of 33,066 healthy men and women aged 20-70 years at recruitment. A lifestyle questionnaire and a validated food frequency questionnaire were administered at study entry (1993-1997). Five dietary patterns were studied: three a priori patterns (the modified Mediterranean Diet Score (mMDS), the WHO-based Healthy Diet Indicator (HDI) and the Dutch Healthy Diet index (DHD-index)) and two a posteriori data-based patterns. QALYs were used as a summary health measure for healthy life expectancy, combining a person's life expectancy with a weight reflecting loss of quality of life associated with having chronic diseases. Results: The mean QALYs of the participants were 74.9 (standard deviation 4.4). A higher mMDS and HDI were associated with a longer life in good health. Participants who had a high mMDS score (6-9) had 0.17 [95% CI, 0.05; 0.30] more QALYs than participants with a low score (0-3), equivalent to two months longer life in good health. Participants with a high HDI score also had more QALYs (0.15 [95% CI, 0.03; 0.27]) than participants with a low HDI score. Conclusion A Mediterranean-type diet and the Healthy Diet Indicator were associated with approximately 2 months longer life in good health. [ABSTRACT FROM AUTHOR]

BackgroundA large trial to investigate the effectiveness of population based screening for chlamydia infections was conducted in the Netherlands in 2008-2012. The trial was register based and consisted of four rounds of screening of women and men in the age groups 16-29 years in three regions in the Netherlands. Data were collected on participation rates and positivity rates per round. A modeling study was conducted to project screening effects for various screening strategies into the future.Methods and findingsWe used a stochastic network simulation model incorporating partnership formation and dissolution, aging and a sexual life course perspective. Trends in baseline rates of chlamydia testing and treatment were used to describe the epidemiological situation before the start of the screening program. Data on participation rates was used to describe screening uptake in rural and urban areas. Simulations were used to project the effectiveness of screening on chlamydia prevalence for a time period of 10 years. In addition, we tested alternative screening strategies, such as including only women, targeting different age groups, and biennial screening. Screening reduced prevalence by about 1% in the first two screening rounds and leveled off after that. Extrapolating observed participation rates into the future indicated very low participation in the long run. Alternative strategies only marginally changed the effectiveness of screening. Higher participation rates as originally foreseen in the program would have succeeded in reducing chlamydia prevalence to very low levels in the long run.ConclusionsDecreasing participation rates over time profoundly impact the effectiveness of population based screening for chlamydia infections. Using data from several consecutive rounds of screening in a simulation model enabled us to assess the future effectiveness of screening on prevalence. If participation rates cannot be kept at a sufficient level, the effectiveness of screening on prevalence will remain limited.

BACKGROUND: Disability-Adjusted Life Years (DALYs) have the advantage that effects on total health instead of on a specific disease incidence or mortality can be estimated. Our aim was to address several methodological points related to the computation of DALYs at an individual level in a follow-up study. METHODS: DALYs were computed for 33,507 men and women aged 20-70 years when participating in the EPIC-NL study in 1993-7. DALYs are the sum of the Years Lost due to Disability (YLD) and the Years of Life Lost (YLL) due to premature mortality. Premature mortality was defined as death before the estimated date of individual Life Expectancy (LE). Different methods to compute LE were compared as well as the effect of different follow-up periods using a two-part model estimating the effect of smoking status on health as an example. RESULTS: During a mean follow-up of 12.4 years, there were 69,245 DALYs due to years lived with a disease or premature death. Current-smokers had lost 1.28 healthy years of their life (1.28 DALYs 95%CI 1.10; 1.46) compared to never-smokers. The outcome varied depending on the method used for estimating LE, completeness of disease and mortality ascertainment and notably the percentage of extinction (duration of follow-up) of the cohort. CONCLUSION: We conclude that the use of DALYs in a cohort study is an appropriate way to assess total disease burden in relation to a determinant. The outcome is sensitive to the LE calculation method and the follow-up duration of the cohort.

BACKGROUND: The costs and benefits of controlling nosocomial spread of antibiotic-resistant bacteria are unknown. METHODS: We developed a mathematical algorithm to determine cost-effectiveness of infection control programs and explored the dynamical interactions between different epidemiological variables and cost-effectiveness. The algorithm includes occurrence of nosocomial infections, attributable mortality, costs and efficacy of infection control and how antibiotic-resistant bacteria affect total number of infections: do infections with antibiotic-resistant bacteria replace infections caused by susceptible bacteria (replacement scenario) or occur in addition to them (addition scenario). Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia was used for illustration using observational data on S. aureus bacteremia (SAB) in our hospital (n = 189 between 2001-2004, all being methicillin-susceptible S. aureus [MSSA]). RESULTS: In the replacement scenario, the costs per life year gained range from 45,912 euros to 6590 euros for attributable mortality rates ranging from 10% to 50%. Using 20,000 euros per life year gained as a threshold, completely preventing MRSA would be cost-effective in the replacement scenario if attributable mortality of MRSA is > or = 21%. In the addition scenario, infection control would be cost saving along the entire range of estimates for attributable mortality. CONCLUSIONS: Cost-effectiveness of controlling antibiotic-resistant bacteria is highly sensitive to the interaction between infections caused by resistant and susceptible bacteria (addition or replacement) and attributable mortality. In our setting, controlling MRSA would be cost saving for the addition scenario but would not be cost-effective in the replacement scenario if attributable mortality would be < 21%.

BackgroundObesity is a major cause of morbidity and mortality and is associated with high medical expenditures. It has been suggested that obesity prevention could result in cost savings. The objective of this study was to estimate the annual and lifetime medical costs attributable to obesity, to compare those to similar costs attributable to smoking, and to discuss the implications for prevention.Methods and findingsWith a simulation model, lifetime health-care costs were estimated for a cohort of obese people aged 20 y at baseline. To assess the impact of obesity, comparisons were made with similar cohorts of smokers and "healthy-living" persons (defined as nonsmokers with a body mass index between 18.5 and 25). Except for relative risk values, all input parameters of the simulation model were based on data from The Netherlands. In sensitivity analyses the effects of epidemiologic parameters and cost definitions were assessed. Until age 56 y, annual health expenditure was highest for obese people. At older ages, smokers incurred higher costs. Because of differences in life expectancy, however, lifetime health expenditure was highest among healthy-living people and lowest for smokers. Obese individuals held an intermediate position. Alternative values of epidemiologic parameters and cost definitions did not alter these conclusions.ConclusionsAlthough effective obesity prevention leads to a decrease in costs of obesity-related diseases, this decrease is offset by cost increases due to diseases unrelated to obesity in life-years gained. Obesity prevention may be an important and cost-effective way of improving public health, but it is not a cure for increasing health expenditures.

Objectives: To evaluate the cost-effectiveness of a tight-control treatment strategy using the handscan (TCHS) compared to using only clinical assessments (TC) and compared to a general non-tight-control treatment strategy (usual care; UC) in early rheumatoid arthritis (RA)., Methods: Data from 299 early RA patients from the CAMERA trial were used. Clinical outcomes were extrapolated to Quality Adjusted Life Years (QALYs) and costs using a Markov model. Costs and QALYs were compared between the TC and UC treatment strategy arm of the CAMERA trial and a simulated tight-control treatment strategy using the handscan (TCHS). Incremental Cost-Effectiveness Ratios (ICERs) were calculated and several scenario analyses performed. All analyses were performed probabilistically to obtain confidence intervals and costs-effectiveness planes and acceptability curves., Results: In TCHS, €4,660 (95% CI -€11,516 to €2,045) was saved and 0.06 (95% CI 0.01 to 0.11) QALYs were gained when compared to UC, with an ICER of €77,670 saved per QALY gained. Ninety-one percent (91%) of simulations resulted in less costs and more QALYs. TCHS resulted in comparable costs or even limited savings €642 (95% CI -€6,903 to €5,601)) and comparable QALYs to TC. In all scenario analyses, TCHS and TC were found to be cost effective as compared to UC., Conclusions: A tight-control treatment strategy is highly cost-effective compared to a non-tight-control approach in early RA. Using the handscan as a monitoring device might facilitate implementation of tight-control treatment strategy at comparable costs and with comparable effects. This approach should be investigated further.