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Background and Objective: Patient heterogeneity is the part of variability that can be explained by certain patient characteristics (e.g. age, disease stage). Population reimbursement decisions that acknowledge patient heterogeneity could potentially save money and increase population health. To date, however, economic evaluations pay only limited attention to patient heterogeneity. The objective of the present paper is to provide a comprehensive overview of the current knowledge regarding patient heterogeneity within economic evaluation of healthcare programmes.Methods: A systematic literature review was performed to identify methodological papers on the topic of patient heterogeneity in economic evaluation. Data were obtained using a keyword search of the PubMed database and manual searches. Handbooks were also included. Relevant data were extracted regarding potential sources of patient heterogeneity, in which of the input parameters of an economic evaluation these occur, methods to acknowledge patient heterogeneity and specific concerns associated with this acknowledgement.Results: A total of 20 articles and five handbooks were included. The relevant sources of patient heterogeneity (demographics, preferences and clinical characteristics) and the input parameters where they occurred (baseline risk, treatment effect, health state utility and resource utilization) were combined in a framework. Methods were derived for the design, analysis and presentation phases of an economic evaluation. Concerns related mainly to the danger of false-positive results and equity issues.Conclusion: By systematically reviewing current knowledge regarding patient heterogeneity within economic evaluations of healthcare programmes, we provide guidance for future economic evaluations. Guidance is provided on which sources of patient heterogeneity to consider, how to acknowledge them in economic evaluation and potential concerns. The improved acknowledgement of patient heterogeneity in future economic evaluations may well improve the efficiency of healthcare. [ABSTRACT FROM AUTHOR]

Background: The MR CLEAN-LATE trial has shown that patient selection for endovascular treatment (EVT) in the late window (6-24 h after onset or last-seen-well) based on the presence of collateral flow on CT-angiography is safe and effective. We aimed to assess the cost-effectiveness of late-window collateral-based EVT-selection compared to best medical management (BMM) over a lifetime horizon (until 95 years of age)., Materials and Methods: A model-based economic evaluation was performed from a societal perspective in The Netherlands. A decision tree was combined with a state-transition (Markov) model. Health states were defined by the modified Rankin Scale (mRS). Initial probabilities at 3-months post-stroke were based on MR CLEAN-LATE data. Transition probabilities were derived from previous literature. Information on short- and long-term resource use and utilities was obtained from a study using MR CLEAN-LATE and cross-sectional data. All costs are expressed in 2022 euros. Costs and quality-adjusted life years (QALYs) were discounted at a rate of 4% and 1.5%, respectively. The effect of parameter uncertainty was assessed using probabilistic sensitivity analysis (PSA)., Results: On average, the EVT strategy cost €159,592 (95% CI: €140,830-€180,154) and generated 3.46 QALYs (95% CI: 3.04-3.90) per patient, whereas the costs and QALYs associated with BMM were €149,935 (95% CI: €130,841-€171,776) and 2.88 (95% CI: 2.48-3.29), respectively. The incremental cost-effectiveness ratio per QALY and the incremental net monetary benefit were €16,442 and €19,710, respectively. At a cost-effectiveness threshold of €50,000/QALY, EVT was cost-effective in 87% of replications., Discussion and Conclusion: Collateral-based selection for late-window EVT is likely cost-effective from a societal perspective in The Netherlands., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: This study was supported by a grant from the Dutch organization for Health research and Health innovation (ZonMw). H.B. received consultation fees from Stryker Neurovascular (paid to the institution). A.P. received an institutional grant from Siemens Healthineers and Bayer Healthcare. W.Z. received consultation fees from Stryker, Nicolab and Cerenovus (paid to the institution), and is a DSMB member of the Philips’ We-Trust study, Anaconda’s Solonda study, and In Extremis study (all funding paid to the institution).

Background: There is growing evidence to support the benefits of transcatheter aortic valve implantation (TAVI) over surgical aortic valve replacement (SAVR) in patients with symptomatic severe aortic stenosis (sSAS) who are at high- or intermediate-risk of surgical mortality. The PARTNER 3 trial showed clinical benefits with SAPIEN 3 TAVI compared with SAVR in patients at low risk of surgical mortality. Whether TAVI is also cost-effective compared with SAVR for low-risk patients in the Dutch healthcare system remains uncertain. This article presents an analysis using PARTNER 3 outcomes and costs data from the Netherlands to inform a cost-utility model and examine cost implications of TAVI over SAVR in a Dutch low-risk population., Methods: A two-stage cost-utility analysis was performed using a published and validated health economic model based on adverse events with both TAVI and SAVR interventions from a published randomized low risk trial dataset, and a Markov model that captured lifetime healthcare costs and patient outcomes post-intervention. The model was adapted using Netherlands-specific cost data to assess the cost-effectiveness of TAVI and SAVR. Uncertainty was addressed using deterministic and probabilistic sensitivity analyses., Results: TAVI generated 0.89 additional quality-adjusted life years (QALYs) at a €4742 increase in costs per patient compared with SAVR over a lifetime time horizon, representing an incremental cost-effectiveness ratio (ICER) of €5346 per QALY gained. Sensitivity analyses confirm robust results, with TAVI remaining cost-effective across several sensitivity analyses., Conclusions: Based on the model results, compared with SAVR, TAVI with SAPIEN 3 appears cost-effective for the treatment of Dutch patients with sSAS who are at low risk of surgical mortality. Qualitative data suggest broader societal benefits are likely and these findings could be used to optimize appropriate intervention selection for this patient population., (© 2024. The Author(s).)

Objectives: Two-thirds of patients do not harbor lymph node (LN) metastases after neoadjuvant chemoradiotherapy (nCRT). Our aim was to explore under which circumstances a selective lymph node dissection (LND) strategy, which selects patients for LND based on the restaging results after nCRT, has added value compared with standard LND in esophageal cancer., Design: A decision tree with state-transition model was developed. Input data on short-term and long-term consequences were derived from literature. Sensitivity analyses were conducted to assess promising scenarios and uncertainty., Setting: Dutch healthcare system., Participants: Hypothetical cohort of esophageal cancer patients who have already received nCRT and are scheduled for esophagectomy., Interventions: A standard LND cohort was compared with a cohort of patients that received selective LND based on the restaging results after nCRT., Main Outcome Measures: Quality-adjusted life years (QALYs), residual LN metastases and LND-related complications., Results: Selective LND could have short-term benefits, that is, a decrease in the number of performed LNDs and LND-related complications. However, this may not outweigh a slight increase in residual LN metastases which negatively impacts QALYs in the long-term. To accomplish equal QALYs as with standard LND, a new surgical strategy should have the same or higher treatment success rate as standard LND, that is, should show equal or less recurrences due to residual LN metastases., Conclusions: The reduction in LND-related complications that is accomplished by selecting patients for LND based on restaging results after nCRT seems not to outweigh a QALY loss in the long-term due to residual LN metastases. Despite the short-term advantages of selective LND, this strategy can only match long-term QALYs of standard LND when its success rate equals the success rate of standard LND., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The substantial technological advancements in next-generation sequencing (NGS), combined with dropping costs, have allowed for a swift diffusion of NGS applications in clinical settings. Although several commercial parties report to have broken the $1000 barrier for sequencing an entire human genome, a valid cost overview for NGS is currently lacking. This study provides a complete, transparent and up-to-date overview of the total costs of different NGS applications., Methods: Cost calculations for targeted gene panels (TGP), whole exome sequencing (WES) and whole genome sequencing (WGS) were based on the Illumina NextSeq500, HiSeq4000, and HiSeqX5 platforms, respectively. To anticipate future developments, sensitivity analyses are performed., Results: Per-sample costs were €1669 for WGS, € 792 for WES and €333 for TGP. To reach the coveted $1000 genome, not only is the long-term and efficient use of the sequencing equipment needed, but also large reductions in capital costs and especially consumable costs are also required., Conclusions: WES and TGP are considerably lower-cost alternatives to WGS. However, this does not imply that these NGS approaches should be preferred in clinical practice, since this should be based on the tradeoff between costs and the expected clinical utility of the approach chosen. The results of the present study contribute to the evaluation of such tradeoffs., (© 2016 American Association for Clinical Chemistry.)

Background: Currently, a cervical esophagogastric anastomosis (CEA) is often performed after minimally invasive esophagectomy (MIE). However, the CEA is associated with a considerable incidence of anastomotic leakage requiring reintervention or reoperation and moderate functional results. An intrathoracic esophagogastric anastomosis (IEA) might reduce the incidence of anastomotic leakage, improve functional results and reduce costs. The objective of the ICAN trial is to compare anastomotic leakage and postoperative morbidity, mortality, quality of life and cost-effectiveness between CEA and IEA after MIE., Methods/design: The ICAN trial is an open randomized controlled multicentre superiority trial, comparing CEA (control group) with IEA (intervention group) after MIE. All patients with esophageal cancer planning to undergo curative MIE are considered for inclusion. A total of 200 patients will be included in the study and randomized between the groups in a 1:1 ratio. The primary outcome is anastomotic leakage requiring reintervention or reoperation, and secondary outcomes are (amongst others) other postoperative complications, new onset of organ failure, length of stay, mortality, benign strictures requiring dilatation, quality of life and cost-effectiveness., Discussion: We hypothesize that an IEA after MIE is associated with a lower incidence of anastomotic leakage requiring reintervention or reoperation than a CEA. The trial is also designed to give answers to additional research questions regarding a possible difference in functional outcome, quality of life and cost-effectiveness., Trial Registration: Netherlands Trial Register: NTR4333 . Registered on 23 December 2013.

Complex paediatric neurology (CPN) patients generally present with non-specific symptoms, such as developmental delay, impaired movement and epilepsy. The diagnostic trajectory in these disorders is usually complicated and long-lasting, and may be burdensome to the patients and their parents. Additionally, as caring for a chronically ill child can be stressful and demanding, parents of these patients may experience impaired health-related quality of life (HRQoL). This study aims to assess parental HRQoL and factors related to it in CPN. Physical and mental HRQoL of 120 parents was measured and compared to the general population using the SF-12 questionnaire. Parents also completed this questionnaire for the measurement of patient HRQoL. Additional questionnaires were used to measure parental uncertainty (Visual Analogue Scale) and worry phenomena (Penn State Worry Questionnaire), and to obtain socio-demographic data. A linear mixed model with random effect was used to investigate which of these variables were associated with parental HRQoL. As compared to the general population, HRQoL of these parents appeared diminished. Fathers showed both lowered physical (51.76, p < 0.05) and mental (49.41, p < 0.01) HRQoL, whereas mothers only showed diminished mental (46.46, p < 0.01) HRQoL. Patient HRQoL and parental worry phenomena were significantly correlated with overall and mental parental HRQoL. The reduction in parental mental HRQoL is alarming, also because children strongly rely on their parents and parental mental health is known to influence children's health. Awareness of these problems among clinicians, and supportive care if needed are important to prevent exacerbation of the problems., (Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Background: Meniscus scaffolds are currently evaluated clinically for their efficacy in preventing the development of osteoarthritis as well as for their efficacy in treating patients with chronic symptoms. Procedural costs, therapeutic consequences, clinical efficacy, and future events should all be considered to maximize the monetary value of this intervention., Purpose: To examine the socioeconomic effect of treating patients with irreparable medial meniscus injuries with a meniscus scaffold., Study Design: Economic and decision analysis; Level of evidence, 2., Methods: Two Markov simulation models for patients with an irreparable medial meniscus injury were developed. Model 1 was used to investigate the lifetime cost-effectiveness of a meniscus scaffold compared with standard partial meniscectomy by the possibility of preventing the development of osteoarthritis. Model 2 was used to investigate the short-term (5-year) cost-effectiveness of a meniscus scaffold compared with standard partial meniscectomy by alleviating clinical symptoms, specifically in chronic patients with previous meniscus surgery. For both models, probabilistic Monte Carlo simulations were applied. Treatment effectiveness was expressed as quality-adjusted life-years (QALYs), while costs (estimated in euros) were assessed from a societal perspective. We assumed €20,000 as a reference value for the willingness to pay per QALY. Next, comprehensive sensitivity analyses were performed to identify the most influential variables on the cost-effectiveness of meniscus scaffolds., Results: Model 1 demonstrated an incremental cost-effectiveness ratio of a meniscus scaffold treatment of €54,463 per QALY (€5991/0.112). A threshold analysis demonstrated that a meniscus scaffold should offer a relative risk reduction of at least 0.34 to become cost-effective, assuming a willingness to pay of €20,000. Decreasing the costs of the meniscus scaffold procedure by 33% (€10,160 instead of €15,233; an absolute change of €5073) resulted in an incremental cost-effectiveness ratio of €7876 per QALY. Model 2 demonstrated an incremental cost-effectiveness ratio of a meniscus scaffold treatment of €297,727 per QALY (€9825/0.033). On the basis of the current efficacy data, a meniscus scaffold provides a relative risk reduction of "limited benefit" postoperatively of 0.37 compared with standard treatment. A threshold analysis revealed that assuming a willingness to pay of €20,000, a meniscus scaffold would not be cost-effective within a period of 5 years. Most influential variables on the cost-effectiveness of meniscus scaffolds were the cost of the scaffold procedure, cost associated with osteoarthritis, and quality of life before and after the scaffold procedure., Conclusion: Results of the current health technology assessment emphasize that the monetary value of meniscus scaffold procedures is very much dependent on a number of influential variables. Therefore, before implementing the technology in the health care system, it is important to critically assess these variables in a relevant context. The models can be improved as additional clinical data regarding the efficacy of the meniscus scaffold become available., (© 2016 The Author(s).)

Objectives: To examine health utilities in patients with cT1-2 oral cavity squamous cell carcinoma following different diagnostic and treatment modalities for the neck and to investigate the relation between shoulder morbidity and health utility., Design: Cross-sectional survey., Setting: Two Dutch hospitals., Participants: Four subgroups of patients with oral cavity cancer who underwent watchful waiting, sentinel lymph node biopsy, elective supraomohyoid neck dissection or therapeutic modified radical neck dissection., Main Outcome Measures: Patients received the EuroQol-5D-3L questionnaire and the shoulder disability questionnaire. Mean health utility, visual analogue scale and shoulder disability scores were calculated., Results: A total of 181 patients (62%) returned the questionnaires. Mean health utilities, adjusted for age, gender and time since treatment were 0.804, 0.863, 0.834 and 0.794 for the watchful waiting, sentinel lymph node biopsy, supraomohyoid neck dissection and modified radical neck dissection subgroups, respectively. Mean shoulder disability scores (higher score means more shoulder complaints) for these subgroups were 8.64, 10.57, 18.92 and 33.66. Patients with shoulder complaints had a mean utility of 0.78 while patients without shoulder complaints had a mean utility of 0.90., Conclusions: This study shows that more invasive procedures appear to result in lower health utility. The high health utility for patients after sentinel lymph node biopsy supports a role for this procedure in patients with oral cancer., (© 2015 John Wiley & Sons Ltd.)

Actinic keratoses (AK) occur frequently; however, real-life clinical data on personalized treatment choice and costs are scarce. This multicentre one-year observational study investigated patient-characteristics, cost and effectiveness of methylaminolaevulinate photodynamic therapy (MAL-PDT), imiquimod (IMI) and 5-fluorour-acil (5-FU) in patients with AKs on the face/scalp. A total of 104 patients preferred MAL-PDT, 106 preferred IMI and 110 preferred 5-FU. At baseline, significant differences between treatment groups were found; most patients were severely affected (mean 32.5 AK in PDT-group, 20.2 in IMI-group, 22.8 in 5-FU-group). A mean reduction in lesions of 81% after MAL-PDT, 82% after IMI and 88% after 5-FU was found after one year. Annual costs were €1,950 for MAL-PDT, €877 for IMI and €738 for 5-FU. These results show that, compared with clinical trials, in the real-life clinical setting AK patients are usually more severely affected and treatment costs are much higher. Furthermore, patient characteristics are important factors in treatment choice.

Background: Women with a history of preeclampsia are at increased risk for future hypertension and cardiovascular disease (CVD); until now it is not clear whether preventive measures are needed., Methods: A decision-analytic Markov model was constructed to evaluate healthcare costs and effects of screening and treatment (100 % compliance) for hypertension post preeclampsia based on the available literature. Cardiovascular events and CVD mortality were defined as health states. Outcomes were measured in absolute costs, events, life-years and quality-adjusted life-years (QALYs). Sensitivity and threshold analyses were performed to address uncertainty., Results: Over a 20-year time horizon, events occurred in 7.2 % of the population after screening, and in 8.5 % of the population without screening. QALYs increased from 16.37 (no screening strategy) to 16.40 (screening strategy), an increment of 0.03 (95 % CI 0.01;0.05) QALYs. Total expected costs were € 8016 in the screening strategy, and € 9087 in the none screening strategy (expected saving of € 1071 (95 % CI - 3146;-87) per person)., Conclusion: Annual hypertension screening and treatment in women with a history of preeclampsia may save costs, for at least a similar quality of life and survival due to prevented CVD compared with standard care.

A growing number of premenopausal women are currently using antithrombotic and/or (dual) antiplatelet therapy for various cardiovascular indications. These may induce or exacerbate abnormal uterine bleeding and more awareness and knowledge among prescribers is required. Heavy and irregular menstrual bleeding is common in women in their forties and may have a variety of underlying causes that require different treatment options. Thus using anticoagulants in premenopausal women demands specific expertise and close collaboration between cardiovascular physicians and gynecologists. In this article we summarize the scope of the problem and provide practical recommendations for the care for young women taking anticoagulants and/or (dual) antiplatelet therapy. We also recommend that more safety data on uterine bleeding with novel anticoagulants in premenopausal women should be obtained., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Diagnostic imaging (DI) is the fastest growing sector in medical expenditures and takes a central role in medical decision-making. The increasing number of various and new imaging technologies induces a growing demand for cost-effectiveness analysis (CEA) in imaging technology assessment. In this article we provide a comprehensive framework of direct and indirect effects that should be considered for CEA in DI, suitable for all imaging modalities. We describe and explain the methodology of decision analytic modelling in six steps aiming to transfer theory of CEA to clinical research by demonstrating key principles of CEA in a practical approach. We thereby provide radiologists with an introduction to the tools necessary to perform and interpret CEA as part of their research and clinical practice., Key Points: • DI influences medical decision making, affecting both costs and health outcome. • This article provides a comprehensive framework for CEA in DI. • A six-step methodology for conducting and interpreting cost-effectiveness modelling is proposed.

Objective: This study evaluates pregnant women's and healthcare professionals' preferences regarding specific prenatal screening and diagnostic test characteristics., Method: A discrete choice experiment was developed to assess preferences for prenatal tests that differed in seven attributes: minimal gestational age, time to test results, level of information, detection rate, false positive rate, miscarriage risk and costs., Results: The questionnaire was completed by 596 (70.2%) pregnant women and 297 (51.7%) healthcare professionals, of whom 507 (85.1%) and 283 (95.3%), respectively, were included in further analyses as their choice behavior indicated prenatal testing was an option to them. Comparison of results showed differences in relative importance attached to attributes, further reflected by differences in willingness to trade between attributes. Pregnant women are willing to accept a less accurate test to obtain more information on fetal chromosomal status or to exclude the risk of procedure-related miscarriage. Healthcare professionals consider level of information and miscarriage risk to be most important as well but put more emphasis on timing and accuracy., Conclusion: Pregnant women and healthcare professionals differ significantly in their preferences regarding prenatal test characteristics. Healthcare professionals should take these differences into consideration when counseling pregnant women on prenatal testing., (© 2015 John Wiley & Sons, Ltd.)

Purpose: Limited evidence exists that optimization of surgical team composition may improve effectiveness of laparoscopic donor nephrectomy (LDN)., Methods: A retrospective cohort study with 541 consecutive LDNs. From 2003 to 2012, surgical team composition was gradually optimized with regard to the surgeons' experience, proficient assistance and the use of fixed teams., Results: Multivariable analysis showed that a surgical team with an experienced surgeon had a significantly shorter operation time (OT) (-18 min, 95% CI -28 to -9), less estimated blood loss (EBL) (-64 mL, 95% CI -108 to -19) and shorter length of stay (LOS) (-1 day, 95% CI -1.6 to 0). Proficient assistance was also independently associated with a shorter OT (-43 min, 95% CI -53 to -33) and reduced EBL (-58 mL, 95% CI -109 to -6), whereas those procedures performed by fixed teams were related to a shorter operation (-50 min, 95% CI -59 to -43) and warm ischemia time (-1.8, 95% CI -2.1 to -1.5), a reduced mean complication grade (-0.14 per patient, 95% CI -0.3 to -0.02) and a shorter LOS (-1.1 day, 95% CI -1.7 to -05). Health care costs for LDN by one staff surgeon with unproficient assistance were 7.707 Euro, whereas costs for LDN by two staff surgeons in fixed teams were 5.614 Euro., Conclusions: Surgical team composition has a major impact on variables that reflect the effectiveness of LDN from the donors' perspective. Health care costs are lower for LDNs performed by two experienced surgeons in fixed team composition. We advocate the use of two experienced surgeons in fixed team composition for LDN.

Background: The diagnostic trajectory of complex paediatric neurology may be long, burdensome, and expensive while its diagnostic yield is frequently modest. Improvement in this trajectory is desirable and might be achieved by innovations such as whole exome sequencing. In order to explore the consequences of implementing them, it is important to map the current pathway. To that end, this study assessed the healthcare resource use and associated costs in this diagnostic trajectory in the Netherlands., Methods: Fifty patients presenting with complex paediatric neurological disorders of a suspected genetic origin were included between September 2011 and March 2012. Data on their healthcare resource utilization were collected from the hospital medical charts. Unit prices were obtained from the Dutch Healthcare Authority, the Dutch Healthcare Insurance Board, and the financial administration of the hospital. Bootstrap simulations were performed to determine mean quantities and costs., Results: The mean duration of the diagnostic trajectory was 40 months. A diagnosis was established in 6% of the patients. On average, patients made 16 physician visits, underwent four imaging and two neurophysiologic tests, and had eight genetic and 16 other tests. Mean bootstrapped costs per patient amounted to €12,475, of which 43% was for genetic tests (€5,321) and 25% for hospital visits (€3,112)., Conclusion: Currently, the diagnostic trajectories of paediatric patients who have complex neurological disease with a strong suspected genetic component are lengthy, resource-intensive, and low-yield. The data from this study provide a backdrop against which the introduction of novel techniques such as whole exome sequencing should be evaluated., (Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Purpose: The objective of this study was to estimate the expected cost-utility and cost-effectiveness of the ketogenic diet (KD), vague nerve stimulation (VNS) and care as usual (CAU), using a decision analytic model with a 5-year time horizon., Methods: A Markov decision analytical model was constructed to estimate the incremental costs, quality-adjusted life years (QALYs) and successfully treated patient (i.e. 50% or more seizure reduction) of the treatment strategies KD, VNS and CAU, from a health care perspective. The base case considered children with intractable epilepsy (i.e. two or more antiepileptic drugs had failed) aged between 1 and 18 years. Data were derived from literature and expert meetings. Deterministic and probabilistic sensitivity analyses were performed., Results: Our results suggest that KD is more effective and less costly, and thus cost-effective compared with VNS, after 12 months. However, compared to CAU, neither KD nor VNS are cost-effective options, they are both more effective but also more expensive (€346,899 and €641,068 per QALY, respectively). At 5 years, VNS is cost-effective compared with KD and CAU (€11,378 and €68,489 per QALY, respectively) and has a 51% probability of being cost-effective at a ceiling ratio of €80,000 per QALY., Conclusions: Our results suggest that on average the benefits of KD and VNS fail to outweigh the costs of the therapies. However, these treatment options should not be ignored in the treatment for intractable epilepsy in individual or specific groups of patients. There is a great need for high quality comparative studies with large patient samples which allow for subgroup analyses, long-term follow-up periods and outcome measures that measure effects beyond seizure frequency (e.g. quality of life). When this new evidence becomes available, reassessment of the cost-effectiveness of KD and VNS in children with intractable epilepsy should be carried out., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objective: Non-invasive prenatal testing (NIPT) using cell-free fetal DNA in maternal plasma has been developed for the detection of fetal aneuploidy. Clinical trials have shown high sensitivity and specificity for trisomy 21 (T21) in both high-risk and average-risk populations. Although its great potential for prenatal medicine is evident, more information regarding the consequences of implementing NIPT in a national programme for prenatal screening is required., Study Design: A decision-analytic model was developed to compare costs and outcomes of current clinical practice in The Netherlands using conventional screening only, with two alternatives: implementing NIPT as an optional secondary screening test for those pregnancies complicated by a high risk for T21, and implementing NIPT as primary screening test, replacing conventional screening. Probability estimates were derived from a systematic review of international literature. Costs were determined from a health-care perspective. Data were analysed to obtain outcomes, total costs, relative costs and incremental cost-effectiveness ratios (ICERs) for the different strategies. Sensitivity analysis was used to assess the impact of assumptions on model results., Results: Implementing NIPT as an optional secondary, or as primary screening test will increase T21 detection rate by 36% (from 46.8% to 63.5%) and 54% (from 46.8% to 72.0%), simultaneously decreasing the average risk of procedure-related miscarriage by 44% (from 0.0168% to 0.0094% per pregnant woman) and 62% (from 0.0168% to 0.0064% per pregnant woman), respectively. None of the strategies clearly dominated: current clinical practice is the least costly, whereas implementing NIPT will cause total costs of the programme to increase by 21% (from €257.09 to €311.74 per pregnant woman), leading to an ICER of k€94 per detected case of T21, when utilised as an optional secondary screening test and by 157% (from €257.09 to €660.94 per pregnant woman), leading to an ICER of k€460 per detected case of T21, when utilised as primary screening test. However, implementing NIPT as triage test did result in the lowest expected relative costs per case of T21 diagnosed (k€141)., Conclusion: NIPT should be implemented in national health care as an optional secondary screening test for those pregnancies complicated by a high risk for T21., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: The current diagnostic strategy using transrectal ultrasound-guided biopsy (TRUSGB) raises concerns regarding overdiagnosis and overtreatment of prostate cancer (PCa). Interest in integrating multiparametric magnetic resonance imaging (MRI) and magnetic resonance-guided biopsy (MRGB) into the diagnostic pathway to reduce overdiagnosis and improve grading is gaining ground, but it remains uncertain whether this image-based strategy is cost-effective., Objective: To determine the cost-effectiveness of multiparametric MRI and MRGB compared with TRUSGB., Design, Setting, and Participants: A combined decision tree and Markov model for men with elevated prostate-specific antigen (>4 ng/ml) was developed. Input data were derived from systematic literature searches, meta-analyses, and expert opinion., Outcome Measurements and Statistical Analysis: Quality-adjusted life years (QALYs) and health care costs of both strategies were modelled over 10 yr after initial suspicion of PCa. Probabilistic and threshold analyses were performed to assess uncertainty., Results and Limitations: Despite uncertainty around the presented cost-effectiveness estimates, our results suggest that the MRI strategy is cost-effective compared with the standard of care. Expected costs per patient were € 2423 for the MRI strategy and € 2392 for the TRUSGB strategy. Corresponding QALYs were higher for the MRI strategy (7.00 versus 6.90), resulting in an incremental cost-effectiveness ratio of € 323 per QALY. Threshold analysis revealed that MRI is cost-effective when sensitivity of MRGB is ≥ 20%. The probability that the MRI strategy is cost-effective is around 80% at willingness to pay thresholds higher than € 2000 per QALY., Conclusions: Total costs of the MRI strategy are almost equal with the standard of care, while reduction of overdiagnosis and overtreatment with the MRI strategy leads to an improvement in quality of life., Patient Summary: We compared costs and quality of life (QoL) of the standard "blind" diagnostic technique with an image-based technique for men with suspicion of prostate cancer. Our results suggest that costs were comparable, with higher QoL for the image-based technique., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Long-term survival can be obtained with local treatment of lung metastases from colorectal cancer. However, it is unclear as to what the optimal local therapy is: surgery, radiofrequency ablation (RFA) or stereotactic radiotherapy (SBRT)., Methods: A systematic review included 27 studies matching with the a priori selection criteria, the most important being ≥50 patients and a follow-up period of ≥24months. No SBRT studies were eligible. The review was therefore conducted on 4 RFA and 23 surgical series., Results: Four of the surgical studies were prospective, all others were retrospective. No randomized trial was found. The reporting of data differed between the studies, which led to difficulties in the analyses. Treatment-related mortality rates for RFA and surgery were 0% and 1.4-2.4%, respectively, whereas morbidity rates were reported inconsistently but seemed the lowest for surgery., Conclusion: Due to the lack of phase III trials, no firm conclusions can be drawn, although most evidence supports surgery as the most effective treatment option. High-quality trials comparing currently used treatment modalities such as SBRT, RFA and surgery are needed to inform treatment decisions., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Between diagnosis and primary treatment of patients with epithelial ovarian cancer (EOC), gaps of several weeks exist. Reducing these time intervals may benefit the patient and may lead to a reduction of costs. We explored the cost-effectiveness of early-initiated treatment of patients with suspected advanced-stage EOC compared with that of current treatment., Methods: A discrete event simulation was used to synthesize all available evidences and to evaluate the health care costs and effects (quality-adjusted life years [QALYs]) of the 2 treatment strategies over lifetime. Overall survival, progression-free survival, health-related quality of life, and costs of the separate events were assumed to remain equal. Other uncertainties were addressed using deterministic and probabilistic sensitivity analyses., Results: The treatment times of current and early-initiated treatment were 27 and 24 weeks, respectively. Early-initiated treatment yielded 3.42 QALYs per patient, for a total expected health care cost of €25,654. Current treatment yielded 3.40 QALYs per patient, for a total expected health care cost of €25,607. This resulted in an incremental cost-effectiveness ratio of €2592 per QALY gained for early-initiated treatment compared with that for current treatment. For the willingness to pay for €30,000 or more per QALY, early-initiated treatment had a 100% probability of being cost-effective compared with current treatment under the previously mentioned assumptions., Conclusions: Given the current evidence, early-initiated treatment of patients with suspected advanced-stage EOC leads to additional QALYs and seems to be cost-effective compared with current treatment.

Purpose: Guidelines advise primary granulocyte colony-stimulating factor (G-CSF) prophylaxis during chemotherapy if risk of febrile neutropenia (FN) is more than 20%, but this comes with considerable costs. We investigated the incremental costs and effects between two treatment strategies of primary pegfilgrastim prophylaxis., Methods: Our economic evaluation used a health care perspective and was based on a randomized study in patients with breast cancer with increased risk of FN, comparing primary G-CSF prophylaxis throughout all chemotherapy cycles (G-CSF 1-6 cycles) with prophylaxis during the first two cycles only (G-CSF 1-2 cycles). Primary outcome was cost effectiveness expressed as costs per patient with episodes of FN prevented., Results: The incidence of FN increased from 10% in the G-CSF 1 to 6 cycles study arm (eight of 84 patients) to 36% in the G-CSF 1 to 2 cycles study arm (30 of 83 patients), whereas the mean total costs decreased from € 20,658 (95% CI, € 20,049 to € 21,247) to € 17,168 (95% CI € 16,239 to € 18,029) per patient, respectively. Chemotherapy and G-CSF determined 80% of the total costs. As expected, FN-related costs were higher in the G-CSF 1 to 2 cycles arm. The incremental cost effectiveness ratio for the G-CSF 1 to 6 cycles arm compared with the G-CSF 1 to 2 cycles arm was € 13,112 per patient with episodes of FN prevented., Conclusion: We conclude that G-CSF prophylaxis throughout all chemotherapy cycles is more effective, but more costly, compared with prophylaxis limited to the first two cycles. Whether G-CSF prophylaxis throughout all chemotherapy cycles is considered cost effective depends on the willingness to pay per patient with episodes of FN prevented.

Introduction: Modified fractionation radiotherapy (RT), delivering multiple fractions per day or shortening the overall treatment time, improves overall survival for non -small-cell lung cancer (NSCLC) patients compared with conventional fractionation RT (CRT). However, its cost effectiveness is unknown. Therefore, we aimed to examine and compare the cost effectiveness of different modified RT schemes and CRT in the curative treatment of unresected NSCLC patients., Methods: A probabilistic Markov model was developed based on individual patient data from the meta-analysis of radiotherapy in lung cancer (N = 2000). Dutch health care costs, quality-adjusted life years (QALYs), and net monetary benefits (NMBs) were compared between two accelerated schemes (very accelerated RT [VART] and moderately accelerated RT [MART]), two hyperfractionated schemes (using an identical (HRT) or higher (HRT) total treatment dose than CRT) and CRT., Results: All modified fractionations were more effective and costlier than CRT (1.12 QALYs, &OV0556;24,360). VART and MART were most effective (1.30 and 1.32 QALYs) and cost &OV0556;25,746 and &OV0556;26,208, respectively. HRT and HRT yielded less QALYs than the accelerated schemes (1.27 and 1.14 QALYs), and cost &OV0556;26,199 and &OV0556;29,683, respectively. MART had the highest NMB (&OV0556;79,322; 95% confidence interval [CI], &OV0556;35,478-&OV0556;133,648) and was the most cost-effective treatment followed by VART (&OV0556;78,347; 95% CI, &OV0556;64,635-&OV0556;92,526). CRT had an NMB of &OV0556;65,125 (95% CI, &OV0556;54,663-&OV0556;75,537). MART had the highest probability of being cost effective (43%), followed by VART (31%), HRT (24%), HRT (2%), and CRT (0%)., Conclusion: Implementing accelerated RT is almost certainly more efficient than current practice CRT and should be recommended as standard RT for the curative treatment of unresected NSCLC patients not receiving concurrent chemo-radiotherapy.

Objectives: Intra-arterial digital subtraction angiography (DSA), magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) are imaging modalities used for diagnostic work-up of non-traumatic subarachnoid haemorrhage. The aim of our study was to compare the cost-effectiveness of MRA, DSA and CTA in the first year after the bleed., Methods: A decision model was used to calculate costs and benefits (in quality-adjusted life-years [QALYs]) that accrued to cohorts of 1,000 patients. Costs and characteristics of diagnostic tests, therapy, patients' quality of life and associated costs were respected. The diagnostic strategy with highest QALYs and lowest costs was considered most cost-effective., Results: DSA was the most effective diagnostic option, yielding on average 0.6039 QALYs (95 % CI, 0.5761-0.6327) per patient, followed by CTA 0.5983 QALYs (95 % CI, 0.5704-0.6278) and MRA 0.5947 QALYs (95 % CI, 0.5674-0.6237). Cost was lowest for DSA (39,808 ; 95 % CI, 37,182-42,663), followed by CTA (40,748 ; 95 % CI, 37,937-43,831) and MRA (41,814 ; 95 % CI, 38,730-45,146). A strategy of CTA followed by DSA if CTA was negative or coiling deemed not feasible, was as effective as DSA alone at average costs of 39,767 (95 % CI, 36,903-42,402)., Conclusion: A combined strategy of CTA and DSA was found to be the most cost-effective diagnostic approach., Main Messages: • We defined a standard model for cost-effectiveness analysis in diagnostic imaging. • Comparing total 1-year health costs and benefits, CTA is superior to MRA. • A strategy of combining CTA and DSA was found to be the most cost-effective diagnostic approach.

Objectives: To assess the cost-effectiveness of five strategies for diagnosing and treating cT1-2N0 oral squamous cell cancer., Materials and Methods: A Markov decision analytic model was used to evaluate the cost-effectiveness of (1) elective neck dissection (END), (2) watchful waiting (WW), (3) gene expression profiling (GEP) followed by neck dissection (ND) or WW, (4) sentinel lymph node (SLN) procedure followed by ND or WW, and (5) GEP and SLN (for positive GEP) followed by ND or WW. Uncertainty was addressed using one-way and probabilistic sensitivity analyses., Results: Base-case analysis showed that SLN procedure followed by ND or WW was the most effective and most cost effective strategy. Compared with direct END the incremental cost effectiveness ratio was €3356 per QALY gained. Uncertainty analysis showed that the model was sensitive to changes in assumed occult metastases incidence and utility values. SLN was found to have the highest probability (66%) of being cost-effective of the five strategies, at a willingness to pay of €80,000 per QALY., Conclusions: Given the current evidence and costs the SLN procedure followed by ND or WW appears to be the most cost effective strategy for diagnosing and treating oral squamous cell cancer patients. Our model provides the foundation for future diagnostic and therapeutic research in this field and shows that further information on quality of life in this population is highly valuable., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Live kidney donation has a clear economical benefit over dialysis and deceased-donor transplantation. Compared with mini-incision open donor nephrectomy, laparoscopic donor nephrectomy (LDN) is considered cost-effective. However, little is known on the cost-effectiveness of hand-assisted retroperitoneoscopic donor nephrectomy (HARP). This study evaluated the cost-effectiveness of HARP versus LDN., Methods: Alongside a randomized controlled trial, the cost-effectiveness of HARP versus LDN was assessed. Eighty-six donors were included in the LDN group and 82 in the HARP group. All in-hospital costs were recorded. During follow-up, return-to-work and other societal costs were documented up to 1 year. The EuroQol-5D questionnaire was administered up to 1 year postoperatively to calculate quality-adjusted life years (QALYs)., Results: Mean total costs from a healthcare perspective were $8935 for HARP and $8650 for LDN (P = 0.25). Mean total costs from a societal perspective were $16,357 for HARP and $16,286 for LDN (P = 0.79). On average, donors completely resumed their daytime jobs on day 54 in the HARP group and on day 52 in the LDN group (P = 0.65). LDN resulted in a gain of 0.005 QALYs., Conclusions: Absolute costs of both procedures are very low and the differences in costs and QALYs between LDN and HARP are very small. Other arguments, such as donor safety and pain, should determine the choice between HARP and LDN.

Objectives: In early stages of development of new medical technologies, there are conceptually separate but related societal decisions to be made concerning adoption, further development (i.e., technical improvement), and research (i.e., clinical trials) of new technologies. This article presents a framework to simultaneously support these three decisions from a societal perspective. The framework is applied to the 70-gene signature, a gene-expression profile for breast cancer, deciding which patients should receive adjuvant systemic therapy after surgery. The "original" signature performed on fresh frozen tissue (70G-FFT) could be further developed to a paraffin-based signature (70G-PAR) to reduce test failures., Methods: A Markov decision model comparing the "current" guideline Adjuvant Online (AO), 70G-FFT, and 70G-PAR was used to simulate 20-year costs and outcomes in a hypothetical cohort in The Netherlands. The 70G-PAR strategy was based on projected data from a comparable technology. Incremental net monetary benefits were calculated to support the adoption decision. Expected net benefit of development for the population and expected net benefit of sampling were calculated to support the development and research decision., Results: The 70G-PAR had the highest net monetary benefit, followed by the 70G-FFT. The population expected net benefit of development amounted to €91 million over 20 years (assuming €250 development costs per patient receiving the test). The expected net benefit of sampling amounted to €61 million for the optimal trial (n = 4000)., Conclusions: We presented a framework to simultaneously support adoption, development, and research decisions in early stages of medical technology development. In this case, the results indicate that there is value in both further development of 70G-FFT into 70G-PAR and further research., (Copyright © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Objective: To review and analyze recommendations from national pharmacoeconomic guidelines with regard to acknowledging patient heterogeneity in economic evaluations., Methods: National pharmacoeconomic guidelines were obtained through the ISPOR Web site. Guidance was extracted by using a developed data extraction sheet. Extracted data were divided into subcategories on the basis of consensus meetings., Results: Of the 26 included guidelines, 20 (77%) advised to identify patient heterogeneity. Most guidelines (77%) provided general methodological advice to acknowledge patient heterogeneity, including justifications for distinguishing subgroups (65%), prespecification of subgroups (42%), or methodology to acknowledge patient heterogeneity (77%). Stratified analysis of cost-effectiveness was most commonly advised (20 guidelines; 77%); however, guidance on the specific application of methods was scarce (9 guidelines; 34%) and generally limited if provided. Guidance to present patient heterogeneity was provided by 15 guidelines (58%), most prominently to describe the definition (31%) and justification (31%) of subgroups., Conclusions: The majority of national pharmacoeconomic guidelines provide guidance on acknowledging patient heterogeneity in economic evaluations. However, because guidance is mostly not specific, its usefulness is limited. This may reflect that the importance of acknowledging patient heterogeneity is usually recognized while there is a lack of consensus on specific methods to acknowledge patient heterogeneity. We advise the further development of national pharmacoeconomic guidelines to provide specific guidance on the identification of patient heterogeneity, methods to acknowledge it, and presenting the results. We present a checklist that can assist in formulating these recommendations. This could facilitate the systematic and transparent handling of patient heterogeneity in economic evaluations worldwide., (Copyright © 2013 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Purpose: To use Normal Tissue Complication Probability (NTCP) models and comparative planning studies to explore the (cost-)effectiveness of swallowing sparing intensity modulated proton radiotherapy (IMPT) compared with swallowing sparing intensity modulated radiotherapy with photons (IMRT) in head and neck cancer (HNC)., Methods and Materials: A Markov model was constructed to examine and compare the costs and quality-adjusted life years (QALYs) of the following strategies: (1) IMPT for all patients; (2) IMRT for all patients; and (3) IMPT if efficient. The assumption of equal survival for IMPT and IMRT in the base case analysis was relaxed in a sensitivity analysis., Results: Intensity modulated proton radiation therapy and IMRT for all patients yielded 6.620 and 6.520 QALYs and cost €50,989 and €41,038, respectively. Intensity modulated proton radiation therapy if efficient yielded 6.563 QALYs and cost €43,650. The incremental cost-effectiveness ratio of IMPT if efficient versus IMRT for all patients was €60,278 per QALY gained. In the sensitivity analysis, IMRT was more effective (0.967 QALYs) and less expensive (€8218) and thus dominated IMPT for all patients., Conclusions: Cost-effectiveness analysis based on normal tissue complication probability models and planning studies proved feasible and informative and enables the analysis of individualized strategies. The increased effectiveness of IMPT does not seem to outweigh the higher costs for all head-and-neck cancer patients. However, when assuming equal survival among both modalities, there seems to be value in identifying those patients for whom IMPT is cost-effective., (Copyright © 2013 Elsevier Inc. All rights reserved.)

To examine the impact of late treatment-related xerostomia and dysphagia on health-related quality of life (HRQOL) in head and neck cancer (HNC) patients after radiotherapy. A multi-center cross-sectional survey was performed. Patients with a follow-up of at least 6months after curative radiotherapy, without evidence of recurrent disease were eligible for inclusion. The Euroqol-5D questionnaire (EQ-5D) was filled out and toxicity was scored and converted to the RTOG scale. The EQ-5D measures generic HRQOL in terms of utility and visual analogue scale (VAS) scores. Missing data on the EQ-5D were imputed using multiple imputation. HRQOL was compared between subgroups of patients with and without toxicity. Subsequently, the impact of xerostomia and dysphagia on HRQOL was analyzed using multivariate regression analyses. Both analyses were performed separately for utility scores and VAS scores. The study population was composed of 396 HNC patients. The average utility and VAS scores were 0.85 (scale 0-1) and 75 (scale 0-100). Subgroups of patients with xerostomia and/or dysphagia showed statistically significantly lower utility and VAS scores (P=0.000-0.022). The multivariate regression model showed that xerostomia and dysphagia were negative predictors of both utility and VAS scores. Other factors which influenced HRQOL in at least one of the two regression models were: sex, tumor location and the addition of surgery to radiotherapy. Xerostomia and dysphagia diminish generic HRQOL. Moreover dysphagia affects patients' HRQOL stronger than xerostomia., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: Health technology assessments (HTAs) intend to inform real-world decisions. They often draw on data from explanatory trials and hence are not always applicable to the decision problem. HTAs may therefore not meet the needs of decision makers. Our objective was to develop and apply a checklist to: 1) systematically frame HTAs in a way that they are applicable to the decision problem; and 2) assess if a decision problem can be informed by an available HTA., Methods: We reviewed published literature to identify factors that should be considered when framing HTAs for resource allocation decisions. The checklist was finalized in collaboration with clinicians and policy makers. We applied the checklist to the economic evaluation of trastuzumab in early breast cancer. We defined a reference case and for each study, retrieved through a systematic review, we examined if each factor was explicitly considered., Results: A checklist was developed with 11 factors (e.g., clinical practice, consequences, and patient use). In the case of trastuzumab, most factors were considered by the 11 retrieved economic evaluations. Two factors, being the inclusion of all relevant comparators and professional use, were considered by none of the studies., Conclusions: We developed a comprehensive checklist with 11 factors to frame HTAs and to assess the applicability of HTAs to resource allocation decisions. Economic evaluations on trastuzumab considered some of these factors, but overlooked others. The proposed checklist assists in systematically considering all factors in developing the conceptual model of an HTA, to make HTAs better reflect the decision problem., (Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Purpose: To synthesize and compare available evidence considering the effectiveness of carbon-ion, proton and photon radiotherapy for head and neck cancer., Methods: A systematic review and meta-analyses were performed to retrieve evidence on tumor control, survival and late treatment toxicity for carbon-ion, proton and the best available photon radiotherapy., Results: In total 86 observational studies (74 photon, 5 carbon-ion and 7 proton) and eight comparative in-silico studies were included. For mucosal malignant melanomas, 5-year survival was significantly higher after carbon-ion therapy compared to conventional photon therapy (44% versus 25%; P-value 0.007). Also, 5-year local control after proton therapy was significantly higher for paranasal and sinonasal cancer compared to intensity modulated photon therapy (88% versus 66%; P-value 0.035). No other statistically significant differences were observed. Although poorly reported, toxicity tended to be less frequent in carbon-ion and proton studies compared to photons. In-silico studies showed a lower dose to the organs at risk, independently of the tumor site., Conclusions: For carbon-ion therapy, the increased survival in mucosal malignant melanomas might suggest an advantage in treating relatively radio-resistant tumors. Except for paranasal and sinonasal cancer, survival and tumor control for proton therapy were generally similar to the best available photon radiotherapy. In agreement with included in-silico studies, limited available clinical data indicates that toxicity tends to be lower for proton compared to photon radiotherapy. Since the overall quantity and quality of data regarding carbon-ion and proton therapy is poor, we recommend the construction of an international particle therapy register to facilitate definitive comparisons., (Copyright © 2010 Elsevier Ltd. All rights reserved.)