Health-related quality of life and productivity costs in breast cancer patients treated with tamoxifen in the Netherlands.

The aim of this study was to describe health-related quality of life (HRQoL) and productivity in Dutch breast cancer patients treated with tamoxifen in an adjuvant setting. Patients who started treatment with a standard dose of tamoxifen and who gave written informed consent, were eligible for participation in this trial. A total of 145 patients were asked to complete a survey at 3 months (T1) and 6 months (T2) after initiation of tamoxifen. HRQoL was measured by the EQ-5D-5L and the FACT-B questionnaire, and productivity by using the iMTA Productivity Costs Questionnaire. At 3 months 137 (95%) and at 6 months 133 (92%) patients responded to the surveys. EQ-5D-5 L utility values for T1 and T2 were 0.81 ± 0.17 and 0.81 ± 0.18, respectively. FACT-B scores for T1 and T2 were 109 ± 17.9 and 108 ± 20.0, respectively. No differences in both EQ-5D-5 L utility and FACT-B scores were found between T1 and T2 (p > 0.05). Age and employment status were statistically significantly associated with FACT-B scores (p = 0.04 and p = 0.03, respectively), indicating that younger and unemployed respondents had lower FACT-B scores. Importantly, both short-term and long-term productivity improved during the first six months of tamoxifen treatment (p < 0.05). Here, short-term productivity losses (consisting of absenteeism, presenteeism and unpaid work) for T1 and T2 were estimated at € 855,- and € 396,-, respectively. Long-term productivity losses (consisting of absenteeism) for T1 and T2 were estimated at € 2876,- and € 1104,-, respectively. In conclusion, this study presents HRQoL scores using different instruments and detailed loss of productivity estimates for breast cancer patients treated with adjuvant endocrine therapy. The results presented here can be used to inform input parameters in health economic evaluations of interventions for patients with breast cancer in the Netherlands and other Western countries and ultimately support decision making.

Variation in the utilization of medical devices across Germany, Italy, and the Netherlands: A multilevel approach.

Variation in healthcare utilization has been discussed extensively, with many studies showing that variation exists, but fewer studies investigating the underlying factors. In our study, we used a logistic multilevel-model at the patient, hospital, and regional levels to investigate (i) the levels to which variation could be attributed and (ii) the hospital and regional factors associated with treatment decisions. To do so, we used hospital discharge records for the years 2012-2016 in Germany and Italy and for 2014-2016 in the Netherlands combined with hospital and regional characteristics in nine case studies. We used a theoretical framework to categorize these case studies into effective, preference-sensitive, and supply-sensitive care. Our results suggest that most variation in the treatment decision can be attributed to the hospital level (e.g., case volume), whereas only a minor part is explained by regional characteristics. Italy had the highest share attributable to the regional level, whereas the Netherlands had the lowest. We observed less variation for procedures in the effective-care category compared to the preference- and supply-sensitive categories. Although our results were heterogeneous, we identified patterns in line with the theoretical framework for treatment categories, underlining the need to address variation differently depending on the category in question.

Therapeutic Drug Monitoring-Guided Adjuvant Tamoxifen Dosing in Patients with Early Breast Cancer: A Cost-Effectiveness Analysis from the Prospective TOTAM Trial.

BACKGROUND AND OBJECTIVES: Endoxifen is the active metabolite of tamoxifen, and a minimal plasma concentration of 16 nM has been suggested as a threshold above which it is effective in reducing the risk of breast cancer recurrence. The aim of the current analysis was to investigate the cost-effectiveness of therapeutic drug monitoring (TDM)-guided tamoxifen dosing. METHODS: A cost-effectiveness analysis was performed from a Dutch healthcare perspective, using a partitioned survival model and a lifetime horizon. The reduction in subtherapeutic treatment following TDM is modelled as improved rates of recurrence-free survival (RFS) and overall survival (OS) in comparison to standard tamoxifen treatment. A probabilistic sensitivity analysis (PSA) and a series of scenario analyses were performed to assess the robustness of the results. RESULTS: Base-case results estimated a total increase in life years and quality-adjusted life years (QALYs) for TDM of 0.40 and 0.53, respectively. Total costs for TDM and standard tamoxifen treatment are €32,893 and €39,524, respectively. The TDM intervention results in both more QALYs and less healthcare costs, indicating a dominating effect for TDM. The PSA results indicate that the probability of TDM being cost-effective is 92% when using a willingness-to-pay threshold of €20,000. CONCLUSIONS: TDM-guided dose optimization of tamoxifen is estimated to save costs and increase QALYs for early breast cancer patients.

Avatrombopag and lusutrombopag for thrombocytopenia in people with chronic liver disease needing an elective procedure: a systematic review and cost-effectiveness analysis.

BACKGROUND: There have been no licensed treatment options in the UK for treating thrombocytopenia in people with chronic liver disease requiring surgery. Established management largely involves platelet transfusion prior to the procedure or as rescue therapy for bleeding due to the procedure. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of two thrombopoietin receptor agonists, avatrombopag (Doptelet®; Dova Pharmaceuticals, Durham, NC, USA) and lusutrombopag (Mulpleta®; Shionogi Inc., London, UK), in addition to established clinical management compared with established clinical management (no thrombopoietin receptor agonist) in the licensed populations. DESIGN: Systematic review and cost-effectiveness analysis. SETTING: Secondary care. PARTICIPANTS: Severe thrombocytopenia (platelet count of < 50,000/µl) in people with chronic liver disease requiring surgery. INTERVENTIONS: Lusutrombopag 3 mg and avatrombopag (60 mg if the baseline platelet count is < 40,000/µl and 40 mg if it is 40,000-< 50,000/µl). MAIN OUTCOME MEASURES: Risk of platelet transfusion and rescue therapy or risk of rescue therapy only. REVIEW METHODS: Systematic review including meta-analysis. English-language and non-English-language articles were obtained from several databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials, all searched from inception to 29 May 2019. ECONOMIC EVALUATION: Model-based cost-effectiveness analysis. RESULTS: From a comprehensive search retrieving 11,305 records, six studies were included. Analysis showed that avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy or rescue therapy only, and mostly with a statistically significant difference (i.e. 95% confidence intervals not overlapping the point of no difference). However, only avatrombopag seemed to be superior to no thrombopoietin receptor agonist in reducing the risk of rescue therapy, although far fewer patients in the lusutrombopag trials than in the avatrombopag trials received rescue therapy. When assessing the cost-effectiveness of lusutrombopag and avatrombopag, it was found that, despite the success of these in avoiding platelet transfusions prior to surgery, the additional long-term gain in quality-adjusted life-years was very small. No thrombopoietin receptor agonist was clearly cheaper than both lusutrombopag and avatrombopag, as the cost savings from avoiding platelet transfusions were more than offset by the drug cost. The probabilistic sensitivity analysis showed that, for all thresholds below £100,000, no thrombopoietin receptor agonist had 100% probability of being cost-effective. LIMITATIONS: Some of the rescue therapy data for lusutrombopag were not available. There were inconsistencies in the avatrombopag data. From the cost-effectiveness point of view, there were several additional important gaps in the evidence required, including the lack of a price for avatrombopag. CONCLUSIONS: Avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy, but they were not cost-effective given the lack of benefit and increase in cost. FUTURE WORK: A head-to-head trial is warranted. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019125311. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 51. See the NIHR Journals Library website for further project information.

Thrombocytopenia, which is a reduction in platelet numbers in the blood, is a common complication of chronic liver disease. It increases the risk of bleeding during procedures including liver biopsy and transplantation. It can delay or prevent procedures, leading to illness and death. Established treatment largely involves platelet transfusion before the procedure or as rescue therapy for bleeding. This report aims to systematically review the clinical effectiveness and estimate the cost-effectiveness of the first two recently licensed treatments, thrombopoietin receptor agonists avatrombopag (Doptelet^®; Dova Pharmaceuticals, Durham, NC, USA) (60 mg if platelet count is < 40,000/µl and 40 mg if platelet count is 40,000­< 50,000/µl) and lusutrombopag (Mulpleta^®; Shionogi Inc., London, UK) (3 mg if platelet count is < 50,000/µl), compared with established treatment. From a comprehensive search, six studies were included. Clinical effectiveness analysis showed that avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy. Only avatrombopag seemed superior to no thrombopoietin receptor agonist in reducing rescue therapy alone. Cost-effectiveness analysis found that lusutrombopag and avatrombopag were more expensive than no thrombopoietin receptor agonist over a lifetime, as the savings from avoiding platelet transfusions were exceeded by the drug cost, and without long-term health benefits. The probabilistic sensitivity analysis, which examined the effect of uncertainty, showed that no thrombopoietin receptor agonist had 100% probability of being cost-effective. Uncertainty about the price of avatrombopag and the content and costs of platelet transfusions and the potential under-reporting of use to estimate platelet transfusion-specific mortality had the greatest impact on results. If the price of avatrombopag was (confidential information has been removed) below the price of lusutrombopag, avatrombopag would become cost saving in the 40,000­< 50,000/µl subgroup. However, although in some scenarios avatrombopag costs could decrease in the 40,000­< 50,000/µl subgroup to around 10% more than the cost of no thrombopoietin receptor agonist, there would be negligible health benefits and the incremental cost-effectiveness ratios would remain very high, meaning that lusutrombopag and avatrombopag would still not be considered cost-effective.

Management of Hardware Related Infections after DBS Surgery: A Cost Analysis.

AIM: To investigate the costs of treating the infection with antibiotics only with the risk of surgery when unsuccessful versus immediate removal followed by re-implantation in patients with deep brain stimulation (DBS) hardware infection. MATERIAL AND METHODS: We calculated the costs of the different strategies through a standard costing procedure. A decision model has been applied to establish the average treatment cost per patient representative for a clinical setting where both strategies are employed. Subsequently, a sensitivity analysis has been performed to assess the influence of clinical assumptions regarding the effectiveness of antibiotics treatment on average treatment costs. RESULTS: The costs of treating a case of DBS hardware infection with immediate internal pulse generator (IPG) replacement surgery were ?29,301 compared to ?9499 for successful antibiotic treatment. For antibiotic treatment followed by IPG replacement surgery the total costs were ?38,741. Antibiotic treatment alone was successful in 44% (4/9) of the included cases of DBS infection, resulting in average treatment costs per patient of ?25,745. Trying to resolve DBS hardware infections initially with antibiotics reduced treatment costs by 12.1%. CONCLUSION: Treatment with antibiotics with the risk of a later removal when unsuccessful was a more valuable strategy in terms of costs when compared to immediate surgical intervention in cases of hardware-related infections in DBS surgeries.

Cost-effectiveness and Budget Impact of Specialized Psychotherapy for Borderline Personality Disorder: A Synthesis of the Evidence.

BACKGROUND: Specialized outpatient psychotherapy for patients with borderline personality disorder (BPD) is expected to reduce their use of other health care resources. It is currently unknown to what extent the costs of providing these interventions can be expected to be offset by a reduction in other health care costs in the Netherlands. To establish the cost-effectiveness and budget impact of specialized outpatient psychotherapy, the estimated incremental costs are synthesized with the estimated incremental effects. We have developed a method for the synthesis of all relevant evidence on clinical effectiveness as well as health care resource use. AIM OF THE STUDY: The aim of this article is to present a method for the synthesis of evidence for cost-effectiveness and budget impact analysis with a specific application to specialized outpatient psychotherapy for borderline personality disorder in the Netherlands. METHODS: A systematic search of the English-language literature is performed to retrieve evidence on the clinical effectiveness and the health care resource use following 12 months of specialized outpatient psychotherapy for borderline personality disorder. The available evidence is used as an input for a model-based economic evaluation. Simulated patient-level data are used to provide overall estimates of the incremental costs and incremental effects, which serve to assess the cost-effectiveness and budget impact of specialized outpatient psychotherapy for borderline personality disorder in the Netherlands. RESULTS: The results indicate that specialized outpatient psychotherapy for BPD can be considered cost-effective and that its scaling up to Dutch national level would require an investment of 2.367 million (95% C.I.: 1,717,000 - 3,272,000) per 1,000 additional patients with BPD. Sensitivity analyses demonstrated the robustness of our findings in light of several uncertain components and assumptions in our calculations, but also their sensitivity to the choice of included studies based on the comparator condition and the assumption of high intervention costs. DISCUSSION: We present a method for the synthesis of evidence from different types of studies in a way that respects the uncertainty surrounding those findings. Limitations of the study pertain to the inclusion of findings from studies with suboptimal designs, the transferability of research findings, and uncertainty regarding the time horizon considered. More research is needed on the sensitivity of our findings to the choice of included studies based on the comparator condition. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: THE results suggest that the provision of specialized outpatient psychotherapy for BPD leads to a reduction in other health care resource use. Overall, the results are promising and encourage future studies on aspects that are currently still uncertain. IMPLICATIONS FOR HEALTH POLICIES: The results may support policy makers in deciding whether or not to allocate health care budget for the provision of specialized outpatient psychotherapy for patients with BPD in the Netherlands. IMPLICATIONS FOR FURTHER RESEARCH: The results provide important directions for future research. This includes the need for future studies to make a comparison between specialized outpatient psychotherapy and treatment as usual and to have longer follow-up time.

Economic evaluation of schema therapy and clarification-oriented psychotherapy for personality disorders: a multicenter, randomized controlled trial.

PURPOSE: To compare from a societal perspective the cost-effectiveness and cost-utility of schema therapy, clarification-oriented psychotherapy, and treatment as usual for patients with avoidant, dependent, obsessive-compulsive, paranoid, histrionic, and/or narcissistic personality disorder. METHOD: A multicenter, randomized controlled trial, single-blind parallel design, was conducted between May 2006 and December 2011 in 12 Dutch mental health institutes. Data from 320 patients (diagnosed according to DSM-IV criteria) randomly assigned to schema therapy (n = 145), treatment as usual (n = 134), or clarification-oriented psychotherapy (n = 41) were analyzed. Costs were repeatedly measured during 36 months by interview and patient registries. Primary outcome measures were proportion of recovered patients as measured with the Structured Clinical Interview for DSM-IV Axis II Personality Disorders for the cost-effectiveness analysis, and quality-adjusted life-years (QALYs) for the cost-utility analysis. Bootstrap replications in the cost-effectiveness and the cost-utility planes were used to estimate the probability that one treatment was more cost-effective than the other. Mixed gamma regression on net monetary benefit for different levels of willingness to pay for extra effects was used as sensitivity analysis. Additional sensitivity analyses were done to assess robustness of the results. RESULTS: Due to higher clinical effects and lower costs, schema therapy was dominant over the other treatments in the cost-effectiveness analyses. Schema therapy has the probability of being the most cost-effective treatment (78% at €0 to 96% at €37,500 [$27,375] willingness to pay per extra recovery). Treatment as usual was more cost-effective than clarification-oriented psychotherapy due to lower costs. In the cost-utility analysis, schema therapy had a stable 75% probability of being cost-effective. Sensitivity analyses confirmed these findings. CONCLUSIONS: The results support the cost-effectiveness of schema therapy but not of clarification-oriented psychotherapy. TRIAL REGISTRATION: Netherlands Trial Register NTR566.

Design of an international multicentre RCT on group schema therapy for borderline personality disorder.

BACKGROUND: Borderline personality disorder (BPD) is a severe and highly prevalent mental disorder. Schema therapy (ST) has been found effective in the treatment of BPD and is commonly delivered through an individual format. A group format (group schema therapy, GST) has also been developed. GST has been found to speed up and amplify the treatment effects found for individual ST. Delivery in a group format may lead to improved cost-effectiveness. An important question is how GST compares to treatment as usual (TAU) and what format for delivery of schema therapy (format A; intensive group therapy only, or format B; a combination of group and individual therapy) produces the best outcomes. METHODS/DESIGN: An international, multicentre randomized controlled trial (RCT) will be conducted with a minimum of fourteen participating centres. Each centre will recruit multiple cohorts of at least sixteen patients. GST formats as well as the orders in which they are delivered to successive cohorts will be balanced. Within countries that contribute an uneven number of sites, the orders of GST formats will be balanced within a difference of one. The RCT is designed to include a minimum of 448 patients with BPD. The primary clinical outcome measure will be BPD severity. Secondary clinical outcome measures will include measures of BPD and general psychiatric symptoms, schemas and schema modes, social functioning and quality of life. Furthermore, an economic evaluation that consists of cost-effectiveness and cost-utility analyses will be performed using a societal perspective. Lastly, additional investigations will be carried out that include an assessment of the integrity of GST, a qualitative study on patients' and therapists' experiences with GST, and studies on variables that might influence the effectiveness of GST. DISCUSSION: This trial will compare GST to TAU for patients with BPD as well as two different formats for the delivery of GST. By combining an evaluation of clinical effectiveness, an economic evaluation and additional investigations, it will contribute to an evidence-based understanding of which treatment should be offered to patients with BPD from clinical, economic, and stakeholders' perspectives. TRIAL REGISTRATION: Netherlands Trial Register NTR2392. Registered 25 June 2010.

Homeostatic plasticity of striatal neurons intrinsic excitability following dopamine depletion.

The striatum is the major input structure of basal ganglia and is involved in adaptive control of behaviour through the selection of relevant informations. Dopaminergic neurons that innervate striatum die in Parkinson disease, leading to inefficient adaptive behaviour. Neuronal activity of striatal medium spiny neurons (MSN) is modulated by dopamine receptors. Although dopamine signalling had received substantial attention, consequences of dopamine depletion on MSN intrinsic excitability remain unclear. Here we show, by performing perforated patch clamp recordings on brain slices, that dopamine depletion leads to an increase in MSN intrinsic excitability through the decrease of an inactivating A-type potassium current, I(A). Despite the large decrease in their excitatory synaptic inputs determined by the decreased dendritic spines density and the increase in minimal current to evoke the first EPSP, this increase in intrinsic excitability resulted in an enhanced responsiveness to their remaining synapses, allowing them to fire similarly or more efficiently following input stimulation than in control condition. Therefore, this increase in intrinsic excitability through the regulation of I(A) represents a form of homeostatic plasticity allowing neurons to compensate for perturbations in synaptic transmission and to promote stability in firing. The present observations show that this homeostatic ability to maintain firing rates within functional range also occurs in pathological conditions, allowing stabilizing neural computation within affected neuronal networks.