Public Preferences for Policies to Promote COVID-19 Vaccination Uptake: A Discrete Choice Experiment in The Netherlands.

OBJECTIVES: The COVID-19 pandemic forms an unprecedented public health, economic, and social crisis. Uptake of vaccination is critical for controlling the pandemic. Nevertheless, vaccination hesitancy is considerable, requiring policies to promote uptake. We investigate Dutch citizens' preferences for policies that aim to promote vaccination through facilitating choice of vaccination, profiling it as the norm, making vaccination more attractive through rewards, or punishing people who reject vaccination. METHODS: We conducted a discrete choice experiment in which 747 respondents were asked to choose between policies to promote vaccination uptake and their impacts on the number of deaths, people with permanent health problems, households with income loss, and a tax increase. RESULTS: Respondents generally had a negative preference for policies that promote vaccination. They particularly disliked policies that punish those who reject the vaccine and were more favorable toward policies that reward vaccination, such as awarding additional rights to vaccinated individuals through vaccination passports. Respondents who reject vaccination were in general much more negative about the policy options than respondents who consider accepting the vaccine. Nevertheless, vaccination passports are supported by both respondents who accept the vaccine, those who reject vaccination, and those who are unsure about vaccination. CONCLUSIONS: This study provides concrete directions for governments attempting to increase the vaccination uptake in ways that are supported by the public. Our results could encourage policy makers to focus on policy options that make vaccination easier and reward people who take the vaccine, as especially the implementation of vaccination passports was supported.

A two arm randomized controlled trial comparing the short and long term effects of an elimination diet and a healthy diet in children with ADHD (TRACE study). Rationale, study design and methods.

BACKGROUND: Food may trigger Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms. Therefore, an elimination diet (ED) might be an effective treatment for children with ADHD. However, earlier studies were criticized for the nature of the control group, potential confounders explaining the observed effects, unsatisfactory blinding, potential risks of nutritional deficiencies and unknown long term and cost-effectiveness. To address these issues, this paper describes the rationale, study design and methods of an ongoing two arm randomized controlled trial (RCT) comparing the short (5 week) and long term (1 year) effects of an elimination diet and a healthy diet compared with care as usual (CAU) in children with ADHD. METHODS: A total of N = 162 children (5-12 years) with ADHD will be randomized to either an ED or a healthy diet. A comparator arm including N = 60 children being solely treated with CAU (e.g. medication) is used to compare the effects found in both dietary groups. The two armed RCT is performed in two youth psychiatry centers in the Netherlands, with randomization within each participating center. The primary outcome measure is response to treatment defined as a ≥ 30% reduction on an ADHD DSM-5 rating scale (SWAN) and/or on an emotion dysregulation rating scale (SDQ: dysregulation profile). This is assessed after 5 weeks of dietary treatment, after which participants continue the diet or not. Secondary outcome measures include the Disruptive Behavior Diagnostic Observational Schedule (DB-DOS), parent and teacher ratings of comorbid symptoms, cognitive assessment (e.g. executive functions), school functioning, physical measurements (e.g. weight), motor activity, sleep pattern, food consumption, nutritional quality of the diet, adherence, parental wellbeing, use of health care resources and cost-effectiveness. Assessments take place at the start of the study (T0), after five weeks (T1), four months (T2), eight months (T3) and 12 months of treatment (T4). T0, T1 and T4 assessments take place at one of the psychiatric centers. T2 and T3 assessments consist of filling out online questionnaires by the parents only. DISCUSSION: This RCT will likely contribute significantly to clinical practice for ADHD by offering insight into the feasibility, nutritional quality, (cost-)effectiveness and long term effects of dietary treatments for ADHD. TRIAL REGISTRATION: www.trialregister.nl, NTR5434. Registered at October 11th, 2015.

Effectiveness of diabetes self-management education via a smartphone application in insulin treated type 2 diabetes patients - design of a randomised controlled trial ('TRIGGER study').

BACKGROUND: Health care providers aim to stimulate self-management in type 2 diabetes (T2DM) patients. However, they have a limited number of patient contacts to do this. With the growing number of T2DM patients, innovative and cost-effective interventions to promote self-management are needed. We aim to evaluate the effectiveness of diabetes self-management education via a smartphone app in T2DM patients on insulin therapy. METHODS: Non-blinded two-arm multi-centre randomised controlled superiority trial with parallel-groups and equal randomisation ('TRIGGER study'). Eligible patients are 40-70 years, on insulin therapy since at least 3 months, with HbA1c > 53 mmol/mol (> 7%). In total 228 patients will be recruited. The intervention group (n = 114) will receive diabetes self-management education via a smartphone app to trigger diabetes self-management: unidirectional text messages, free of charge, evidence and psychological theory based, with regard to dietary habits, physical activity, hypoglycaemia and glucose variability. Patients choose their preferred frequency (two to six times per week), topics (two or three additionally to hypoglycaemia, which is an obligatory topic), and duration (6 or 9 months). The control group (n = 114) will receive care-as-usual. The primary study endpoint is the HbA1c level after a follow-up of 6 months. The percentage of patients who achieve an HbA1c level ≤ 53 mmol/mol (≤7%) without hypoglycaemia (plasma glucose < 3.5 mmol/L (< 63 mg/dL)) is a co-primary outcome. Secondary outcomes are body mass index, waist circumference, insulin dose, lipid profile, blood pressure, number of hypoglycaemic events, glycaemic variability, self-management (SDSCA), food habits (FFQ), physical activity (IPAQ), health status (EQ-5D-5 L, SF36), diabetes-dependent quality of life (ADDQoL), diabetes treatment satisfaction (DTSQ), satisfaction with the app, the cost-effectiveness of the intervention after 3 months, and sustainability of the intervention effect (3 months extra follow-up in intervention group to compare prolonged to discontinued use of the app). We will use the intention-to-treat principle to analyse data. DISCUSSION: Innovative solutions are needed to improve the (cost-) effectiveness of self-management for the increasing number of T2DM patients. This trial will provide evidence on the effectiveness of a newly developed smartphone app, designed to trigger diabetes self-management. TRIAL REGISTRATION: Dutch Trial Register NTR5515 , registration date: 18 November 2015 (prospectively registered).

Systematic Review of Health Economic Impact Evaluations of Risk Prediction Models: Stop Developing, Start Evaluating.

BACKGROUND: Although health economic evaluations (HEEs) are increasingly common for therapeutic interventions, they appear to be rare for the use of risk prediction models (PMs). OBJECTIVES: To evaluate the current state of HEEs of PMs by performing a comprehensive systematic review. METHODS: Four databases were searched for HEEs of PM-based strategies. Two reviewers independently selected eligible articles. A checklist was compiled to score items focusing on general characteristics of HEEs of PMs, model characteristics and quality of HEEs, evidence on PMs typically used in the HEEs, and the specific challenges in performing HEEs of PMs. RESULTS: After screening 791 abstracts, 171 full texts, and reference checking, 40 eligible HEEs evaluating 60 PMs were identified. In these HEEs, PM strategies were compared with current practice (n = 32; 80%), to other stratification methods for patient management (n = 19; 48%), to an extended PM (n = 9; 23%), or to alternative PMs (n = 5; 13%). The PMs guided decisions on treatment (n = 42; 70%), further testing (n = 18; 30%), or treatment prioritization (n = 4; 7%). For 36 (60%) PMs, only a single decision threshold was evaluated. Costs of risk prediction were ignored for 28 (46%) PMs. Uncertainty in outcomes was assessed using probabilistic sensitivity analyses in 22 (55%) HEEs. CONCLUSIONS: Despite the huge number of PMs in the medical literature, HEE of PMs remains rare. In addition, we observed great variety in their quality and methodology, which may complicate interpretation of HEE results and implementation of PMs in practice. Guidance on HEE of PMs could encourage and standardize their application and enhance methodological quality, thereby improving adequate use of PM strategies.

Costs and benefits of rapid screening of methicillin-resistant Staphylococcus aureus carriage in intensive care units: a prospective multicenter study.

INTRODUCTION: Pre-emptive isolation of suspected methicillin-resistant Staphylococcus aureus (MRSA) carriers is a cornerstone of successful MRSA control policies. Implementation of such strategies is hampered when using conventional cultures with diagnostic delays of three to five days, as many non-carriers remain unnecessarily isolated. Rapid diagnostic testing (RDT) reduces the amount of unnecessary isolation days, but costs and benefits have not been accurately determined in intensive care units (ICUs). METHODS: Embedded in a multi-center hospital-wide study in 12 Dutch hospitals we quantified cost per isolation day avoided using RDT for MRSA, added to conventional cultures, in ICUs. BD GeneOhm™ MRSA PCR (IDI) and Xpert MRSA (GeneXpert) were subsequently used during 17 and 14 months, and their test characteristics were calculated with conventional culture results as reference. We calculated the number of pre-emptive isolation days avoided and incremental costs of adding RDT. RESULTS: A total of 163 patients at risk for MRSA carriage were screened and MRSA prevalence was 3.1% (n=5). Duration of isolation was 27.6 and 21.4 hours with IDI and GeneXpert, respectively, and would have been 96.0 hours when based on conventional cultures. The negative predictive value was 100% for both tests. Numbers of isolation days were reduced by 44.3% with PCR-based screening at the additional costs of €327.84 (IDI) and €252.14 (GeneXpert) per patient screened. Costs per isolation day avoided were €136.04 (IDI) and €121.76 (GeneXpert). CONCLUSIONS: In a low endemic setting for MRSA, RDT safely reduced the number of unnecessary isolation days on ICUs by 44%, at the costs of €121.76 to €136.04 per isolation day avoided.

A study protocol for quantifying patient preferences in neuromuscular disorders: a case study of the IMI PREFER Project.

Objectives: Patient preference studies are increasingly used to inform decision-making during the medical product lifecycle but are rarely used to inform early stages of drug development.  The primary aim of this study is to quantify treatment preferences of patients with neuromuscular disorders, which represent serious and debilitating conditions with limited or no treatment options available. Methods: This quantitative patient preferences study was designed as an online survey, with a cross-over design.  This study will target two different diseases from the neuromuscular disorders disease group, myotonic dystrophy type 1 (DM1) and mitochondrial myopathies (MM). Despite having different physio-pathological pathways both DM1 and MM manifest in a clinically similar manner and may benefit from similar treatment options.  The sample will be stratified into three subgroups: two patient groups differentiated by age of symptom onset and one caregivers group.   Each subgroup will be randomly assigned to complete two of three different preference elicitation methods at two different time points: Q-methodology survey, discrete choice experiment, and best-worst scaling type 2, allowing cross-comparisons of the results across each study time within participants and within elicitation methods. Additional variables such as sociodemographic, clinical and health literacy will be collected to enable analysis of potential heterogeneity. Ethics and Dissemination: This study protocol has undergone ethical review and approval by the Newcastle University R&D Ethics Committee (Ref: 15169/2018). All participants will be invited to give electronic informed consent to take part in the study prior accessing the online survey. All electronic data will be anonymised prior analysis. This study is part of the Patient Preferences in Benefit-Risk Assessments during the Drug Life Cycle (IMI-PREFER) project, a public-private collaborative research project aiming to develop expert and evidence-based recommendations on how and when patient preferences can be assessed and used to inform medical product decision making.

Chronically ill patients' preferences for a financial incentive in a lifestyle intervention. Results of a discrete choice experiment.

BACKGROUND: The preferences of diabetes type 2 patients and cardiovascular disease patients for a financial incentive added to a specified combined lifestyle intervention were investigated. METHODS: A discrete choice experiment questionnaire was filled out by 290 diabetes type 2 patients (response rate 29.9%). Panel-mixed-logit models were used to estimate the preferences for a financial incentive. Potential uptake rates of different financial incentives and relative importance scores of the included attributes were estimated. Included attributes and levels were: form of the incentive (cash money and different types of vouchers), value of the incentive (ranging from 15 to 100 euros), moment the incentive is received (start, halfway, after finishing the intervention) and prerequisite for receiving the incentive (registration, attendance or results at group or individual level). RESULTS: Prerequisites for receiving the financial incentive were the most important attribute, according to the respondents. Potential uptake rates for different financial incentives ranged between 37.9% and 58.8%. The latter uptake rate was associated with a financial incentive consisting of cash money with a value of €100 that is handed out after completing the lifestyle program with the prerequisite that the participant attended at least 75% of the scheduled meetings. CONCLUSIONS: The potential uptake of the different financial incentives varied between 37.9% and 58.8%. The value of the incentive does not significantly influence the potential uptake. However, the potential uptake and associated potential effect of the financial incentive is influenced by the type of financial incentive. The preferred type of incentive is €100 in cash money, awarded after completing the lifestyle program if the participant attended at least 75% of the scheduled meetings.

Fast-track Radioiodine Ablation Therapy After Thyroidectomy Reduces Sick Leave in Patients With Differentiated Thyroid Cancer (FASTHYNA Trial).

BACKGROUND: Recombinant human thyroid stimulating hormone (RhTSH) aided radioiodine ablative therapy (RIT) is current-day practice in the treatment of differentiated thyroid cancer (DTC). It is often planned 4 to 6 weeks after surgery or sometimes even longer (standard protocol). The RhTSH-aided RIT, however, has the advantage that it can be planned shortly after thyroidectomy. The FASTHYNA trial was designed to test the hypothesis that RIT 1 week after thyroidectomy (fast-track protocol) results in a significant reduction of sick leave with lower societal costs and with a better quality of life (QOL) compared with the current standard treatment. METHODS: In a randomized, multicenter trial, we included patients with differentiated thyroid cancer, stage T1-3 N0-1 M0-x, who were treated with a total or completion thyroidectomy, with a paid job of at least 12 hours per week. The primary study end point was days of sick leave reported from time of surgery. Secondary end points were QOL and societal costs associated with absence from work. RESULTS: Twenty patients were eligible for inclusion between November 2013 and May 2016. Significant decreases in mean duration of sick leave in the fast-track group versus the standard care group (115 and 280 hours, respectively, P = 0.02) and in costs associated with productivity losses (&OV0556;4070.77 vs &OV0556;9202.90, P = 0.02) were found. There were no significant differences in QOL between both groups. CONCLUSIONS: The trial showed a significant reduction in sick leave and in societal costs in the fast-track group without a deterioration of QOL. Therefore, fast-track ablation is desirable. TRIAL REGISTRATION: Netherlands trial register: NTR 3933.

Economic evaluations of cholesterol-lowering drugs: a critical and systematic review.

The wide availability of economic evaluations and their increasing importance for decision making emphasises the need for economic evaluations that are methodologically sound. The aim of this review was to provide users of economic evaluations of cholesterol-lowering drugs with an insight into the quality of these evaluations. By focusing on the most relevant studies, the gap between research and policy making may be narrowed. A systematic review was conducted. All Dutch and English publications on economic evaluations of cholesterol-lowering drugs were identified by searching PubMed, the Centre for Reviews and Dissemination database (CRD), the NHS Economic Evaluation Database (NHS EED), the Health Technology Assessment database (HTA) and the Database of Abstracts of Reviews of Effects (DARE). A search strategy was set up to identify the articles to be included. The quality of these articles was assessed using Drummond's checklists. The scoring was performed by at least two reviewers. When necessary, disagreement between these reviewers was decided upon in a consensus meeting. We calculated an average quality score for the included articles. The search identified 1390 articles, of which 23 were included. Most studies measured the costs per life-year gained. The overall score per study was disappointing and varied between 2.7 and 7.7, with an average of 5.5. Most studies scored high on the measurement of costs and consequences, whereas the establishment of effectiveness left room for improvement. Only two studies included a well performed incremental analysis. This study noted an increase of quality of economic evaluations over time, suggesting the value of cost-effectiveness studies for policy decisions increases over time. In general, piggy-back evaluations tended to score higher on quality and may therefore be more valuable in decision making.

Effectiveness and cost-effectiveness of nationwide campaigns for awareness and case finding of hepatitis C targeted at people who inject drugs and the general population in the Netherlands.

BACKGROUND: Hepatitis C virus infection (HCV) is a serious, but underdiagnosed disease that can generally be treated successfully. Therefore, a nationwide HCV awareness campaign was implemented in the Netherlands targeting people who inject drugs (PWID) in addiction care ('PWID intervention') and high-risk groups in the general population ('public intervention'). The objective of this study is to assess the effectiveness and cost-effectiveness of the interventions used in this campaign. METHODS: For the 'PWID' intervention, all addiction care centres in the Netherlands provided proactive individual HCV consultation and testing. The 'public intervention' consisted of health education through mass media and instruction of health care professionals. A Markov chain model was used to estimate incremental cost-effectiveness ratios (ICER, cost per QALY gained). We included a 'DAA treatment' scenario to estimate the effect of these treatment strategies on cost-effectiveness. RESULTS: The 'PWID intervention' identified 257 additional HCV-carriers. The ICER was €9056 (95% CI: €6043-€13,523) when compared to 'no intervention'. The 'public intervention' identified 38 additional HCV-carriers. The ICER was €18,421 (95% CI: €7376-€25,490,119) when compared to 'no intervention'. Probabilistic sensitivity analysis showed that the probability that the 'PWID intervention' was cost-effective was 100%. It also showed a probability of 34% that the 'public intervention' did not exceed the Dutch threshold for cost-effectiveness (€20,000). New treatment regimens are likely to improve cost-effectiveness of this strategy. CONCLUSION: In a nationwide HCV awareness and case finding campaign, the intervention targeting PWID was effective and cost-effective. An intervention targeting risk groups in the general population showed only a modest effect and is therefore less likely to be cost-effective.

Drug costs associated with non-adherence to cholesterol management guidelines for primary prevention of cardiovascular disease in an elderly population: the Rotterdam study.

BACKGROUND: In The Netherlands, costs of HMG-CoA reductase inhibitor (statin) use have recently increased sharply compared with costs of other drugs. However, several studies have established both undertreatment and non-guidelines-indicated treatment with statins, suggesting a suboptimal use of resources. OBJECTIVE: To estimate the drug costs associated with non-guidelines-indicated treatment and undertreatment with statins in an elderly population. PATIENTS AND SETTING: Data were obtained from the Rotterdam Study, a population-based prospective cohort study which began in 1990 with 7983 participants aged > or =55 years. Subjects with a history of cardiovascular disease (CVD) were excluded. Pharmacy records were used to assess patterns of medication use in daily medical practice. MAIN OUTCOME MEASURE: Non-guidelines-indicated treatment and undertreatment with statins were established in relation to Dutch cholesterol management guidelines for all participants. We calculated the costs of statin therapy associated with non-guidelines-indicated treatment, and the costs of statins if all those undertreated were to receive statins. The results were projected on to the Dutch population to determine the economic implications of non-adherence to cholesterol management guidelines in the elderly. RESULTS: Of the participants who started treatment with statins for the primary prevention of CVD during follow-up, 69% received non-guidelines-indicated treatment. More men (7.5%) were undertreated than women (1.6%) and more women (6.2%) received non-guidelines-indicated treatment than men (1.5%). Among the participants without CVD who were still alive at 1 January 2002, 14% were eligible for statin therapy but were untreated. After projection of the prevalence of non-guidelines-indicated treatment and undertreatment to the Dutch population, the absolute costs for non-guidelines-indicated treatment with statins in 2005 were estimated to be approximately 23 million euro(uncertainty limits [UL]: 19-28 million euro), while the cost to eliminate undertreatment was also 23 million euro (UL: 19-28 million euro). CONCLUSION: Reallocation of resources used for statin therapy from those receiving non-guidelines-indicated treatment to those being undertreated could lead to a more efficient use of resources.

Influence of early goal-directed therapy using arterial waveform analysis on major complications after high-risk abdominal surgery: study protocol for a multicenter randomized controlled superiority trial.

BACKGROUND: Early goal-directed therapy refers to the use of predefined hemodynamic goals to optimize tissue oxygen delivery in critically ill patients. Its application in high-risk abdominal surgery is, however, hindered by safety concerns and practical limitations of perioperative hemodynamic monitoring. Arterial waveform analysis provides an easy, minimally invasive alternative to conventional monitoring techniques, and could be valuable in early goal-directed strategies. We therefore investigate the effects of early goal-directed therapy using arterial waveform analysis on complications, quality of life and healthcare costs after high-risk abdominal surgery. METHODS/DESIGN: In this multicenter, randomized, controlled superiority trial, 542 patients scheduled for elective, high-risk abdominal surgery will be included. Patients are allocated to standard care (control group) or early goal-directed therapy (intervention group) using a randomization procedure stratified by center and type of surgery. In the control group, standard perioperative hemodynamic monitoring is applied. In the intervention group, early goal-directed therapy is added to standard care, based on continuous monitoring of cardiac output with arterial waveform analysis. A treatment algorithm is used as guidance for fluid and inotropic therapy to maintain cardiac output above a preset, age-dependent target value. The primary outcome measure is a combined endpoint of major complications in the first 30 days after the operation, including mortality. Secondary endpoints are length of stay in the hospital, length of stay in the intensive care or post-anesthesia care unit, the number of minor complications, quality of life, cost-effectiveness and one-year mortality and morbidity. DISCUSSION: Before the start of the study, hemodynamic optimization by early goal-directed therapy with arterial waveform analysis had only been investigated in small, single-center studies, including minor complications as primary endpoint. Moreover, these studies did not include quality of life, healthcare costs, and long-term outcome in their analysis. As a result, the definitive role of arterial waveform analysis in the perioperative hemodynamic assessment and care for high-risk surgical patients is unknown, which gave rise to the present trial. Patient inclusion started in May 2012 and is expected to end in 2016. TRIAL REGISTRATION: This trial was registered in the Dutch Trial Register (registration number NTR3380) on 3 April 2012.

Model based analysis of hepatitis B vaccination strategies in the Netherlands.

We used a mathematical model for the transmission of hepatitis B infection to compare the effectiveness of different vaccination strategies in the Netherlands. Vaccination of children of immigrants from high and medium endemic countries is an effective strategy in countries with substantial immigration of carriers from high and medium endemic countries. A targeted vaccination programme for sexually highly active risk groups has a moderate additional effect if continued over a long time period. Universal vaccination has the largest effect on the incidence of new infections at the cost of having to vaccinate many more individuals than in targeted programmes. The impact on the prevalence of chronic hepatitis B infection, however, remains limited.

A literature review of assumptions on test characteristics and adherence in economic evaluations of colonoscopy and CT-colonography screening.

Colorectal cancer screening is an effective public health strategy for decreasing colorectal cancer mortality. Since many screening modalities exist, it needs to be determined what the most cost-effective strategy is. The aim of this review is to summarise the available cost-effectiveness evidence for colonoscopy versus CT-colonography screening, and to pay special attention to assumptions regarding test characteristics and adherence. A literature search resulted in twelve economic evaluations that could be included in the review. The incremental cost-effectiveness ratios of colonoscopy and CT-colonography versus no screening remained under 20,000 euro and 30,000 euro per life year gained, respectively. Although, both screening modalities were cost-effective according to most international thresholds, in most of the economic evaluations colonoscopy seemed more cost-effective than colonography screening. In many studies, model assumptions on major parameters (e.g. screening uptake) were more positive than real life data suggest. None of the models included indirect costs, which disproportionally favoured the relative cost-effectiveness of colonoscopy. For a good comparison of both screening methods, it is necessary that the assumptions used in economic evaluations are realistic, and include all costs.

The epidemiology of varicella and herpes zoster in The Netherlands: implications for varicella zoster virus vaccination.

We studied the epidemiology of varicella (chickenpox) and herpes zoster (shingles) in The Netherlands to assess the desirability to implement routine varicella zoster virus vaccination in The Netherlands. Data on seroprevalence of varicella zoster virus in the general population (1995-1996), consultations of general practitioners for varicella (2000-2002) and herpes zoster (1998-2001) and hospital admissions due to varicella (1994-2001) and herpes zoster (1994-2001) in The Netherlands were analysed. The seropositivity increased sharply with age from 18.4% for both 0- and 1-year-olds, to 48.9%, 59.0%, 75.7% and 93.0% for 2-, 3-, 4- and 5-year-olds, respectively, and varied between 97.5% and 100% for older age groups. The average annual incidence of GP-consultations amounted to 253.5 and 325.0 per 100,000 for varicella and herpes zoster, respectively. The incidence of hospital admission due to varicella and herpes zoster was 1.3 (2.3 including side diagnosis) and 2.7 (5.8) per 100,000, respectively. Whilst for varicella, the incidence of GP-consultations and hospital admissions were highest in childhood, for herpes zoster, these were highest in elderly. Insight into epidemiology of varicella zoster is needed for the assessment of the desirability of introduction of routine varicella zoster vaccination.