Publications

Background: Stroke is the second leading cause of death worldwide and the third leading cause of death and disability combined. Among ischemic strokes, 25 % to 40 % are classified as cryptogenic, with patent foramen ovale (PFO) identified as a potential underlying cause. PFO is found in 25 % of the general population. Despite the significant occurrence of PFO-associated strokes, the associated costs remain largely unexplored.

Aim: This study aimed to evaluate the annual economic burden of PFO-associated stroke in the US.

Methods: A cost-of-illness study was performed, encompassing the direct and indirect costs of PFO-associated stroke on both society and the healthcare system. The model adopted a top-down approach and a one-year, US societal perspective. A payer perspective and bottom-up costing approach were included as scenario analyses. Data was obtained by a targeted literature review.

Results: The societal model, assuming 32.5 % cryptogenic strokes, incurs an annual cost of over $1.3 billion in the US, with over $1.0 billion coming from new strokes and over $300 million from recurrent strokes. The majority of the costs are indirect—50 % from productivity losses due to premature death and 27 % from other productivity losses. Direct costs constitute 23 % of the total. From the payer perspective, the annual costs for PFO- associated strokes in the US were estimated at $302 million, with hospitalization costs comprising 44 %, followed by prescriptions and outpatient care at 19 % and 16 %, respectively.

Conclusion: The economic burden of PFO-associated strokes in the US is substantial, exceeding $1.3 billion per year. Different types of medical management or surgical treatments for PFO-associated stroke could lead to gains in both costs and health outcomes.

Background: Chikungunya virus (CHIKV), transmitted through Aedes mosquitoes, has witnessed a global surge in distribution and outbreaks, posing a significant public health threat. This study conducted two systematic literature reviews (SLRs) to examine the socio-economic burden associated with chikungunya.

Methods: Two SLRs were conducted employing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 (PRISMA 2020) standards. The SLRs covered electronic databases, grey literature, and bibliographic searches. Inclusion criteria were guided by the PICOS (Population, Intervention, Comparator, Outcomes, Study type) framework.

Findings: A total of 34 studies on cost and resource use and 37 studies on health-related quality of life (HRQoL) were included. Direct costs, driven by hospitalization, consultations, diagnostics, and drugs, were frequently reported, with significant variability across studies. Indirect costs, mainly attributed to absenteeism, constituted a substantial portion of the total economic burden. HRQoL studies consistently revealed high pain levels and diminished physical functioning among chikungunya patients, particularly in chronic cases, where these impacts persisted for months to years.

Conclusions: This study highlights the significant economic and public health impact of chikungunya, driven by high treatment costs, productivity losses, and chronic disability. Despite the severity of the disease, limited awareness regarding the severity and economic burden, particularly in resource-limited regions, persists. Our findings underscore the need for targeted public health strategies, standardized management approaches, and increased research to better understand the socio-economic burden of the disease and inform effective interventions.

Background: Given their crucial role in vaccine assessment, National Immunization Technical Advisory Groups (NITAGs) should be considered in the Regulation on Health Technology Assessment (EU HTAR) to maximize the benefits of the EU HTAR for vaccines. This review and perspective piece identifies the gaps arising from NITAGs potential lack of involvement and proposes strategies for involving them.

Methods: A targeted literature and guideline review was conducted to evaluate NITAGs’ current and future role in relation to the EU HTAR. The impact of the EU HTAR on diverse national HTA frameworks was explored in a three-country case study. Recommendations were developed to leverage strengths and address weaknesses to ensure consistent and cohesive vaccine assessments.

Results: The case study revealed potential overlaps between NITAGs and the EU HTAR, particularly regarding horizon scanning and joint scientific consultations. The involvement of NITAGs in national assessments varies, influencing how well joint clinical assessment reports will ultimately align with and be applicable to individual Member States.

Conclusions: Stronger consideration of vaccines within the EU HTAR and NITAG involvement can streamline assessments, reduce duplication, and improve alignment between European and national processes. Strategic actions, including capacity building and collaborations between NITAGs, are key in facilitating this process.

Objectives: Evidentiary requirements for relative effectiveness assessment vary among European health technology assessment (HTA) bodies, affecting the time to HTA decision-making and potentially delaying time to patient access. Improved alignment may reduce this time; therefore, we aim to analyze the differences in evidentiary requirements for oncology drug assessments among European HTA bodies and provide recommendations toward an increased alignment.

Methods: Interviews were conducted with stakeholders in drug assessments of Italy, the Netherlands, Poland, Portugal, England and Wales, and Sweden about evidentiary requirements for several subdomains to identify differences and obtain recommendations for addressing differences. The interview results were analyzed on degrees of evidence acceptability per HTA body and alignment on evidentiary requirements among HTA bodies.

Results: Subdomains demonstrating noteworthy differences concerned the acceptability of extrapolation to other populations, class effects, progression-free survival and (other) surrogate endpoints as outcomes, the absence of quality-of-life data, single-arm trials, cross-over trial designs, short trial duration, and the clinical relevance of effect size.

Conclusion: Alignment can be enhanced to reduce time to decision-making and to improve equity in patient access. Proposed recommendations to achieve this included joint early dialogues, intensified collaboration and exchange between countries, joint relative effectiveness assessments, and the use of access agreements.

Background: Chronic migraine (CM) is the most severe and burdensome subtype of migraine. Fremanezumab is a monoclonal antibody that targets the calcitonin gene-related peptide pathway as a migraine preventive therapy. This study aimed to conduct a cost-effectiveness analysis of fremanezumab from a societal perspective in the Netherlands, using a Markov cohort simulation model.

Methods: The base-case cost-effectiveness analysis adhered to the Netherlands Authority guidelines. Fremanezumab was compared with best supportive care (BSC; acute migraine treatment only) in patients with CM and an inadequate response to topiramate or valproate and onabotulinumtoxinA (Dutch patient group [DPG]). A supportive analysis was conducted in the broader group of CM patients with prior inadequate response to 2-4 different classes of migraine preventive treatments. One-way sensitivity, probabilistic sensitivity, and scenario analyses were conducted.

Results: Over a lifetime horizon, fremanezumab is cost saving compared with BSC in the DPG (saving of €2514 per patient) and led to an increase of 1.45 quality-adjusted life-years (QALYs). In the broader supportive analysis, fremanezumab was cost effective compared with BSC, with an incremental cost-effectiveness ratio of €2547/QALY gained. Fremanezumab remained cost effective in all sensitivity and scenario analyses.

Conclusion: In comparison to BSC, fremanezumab is cost saving in the DPG and cost effective in the broader population.

With the increasing pipeline of cell and gene therapies (CGTs) and the expected surge in the number of approvals, understanding the market access landscape becomes crucial for timely patient access. This study evaluates the challenges Dutch stakeholders encounter in CGT market access, offering insights for improving time-to-patient access. A traditional literature review was conducted to identify market access challenges and solutions for CGTs. Based on the findings, participants for semi-structured interviews, designed using an interview guide adapted to the Dutch context, were selected to capture diverse perspectives on market access. This review included 124 relevant articles out of 2449, covering several aspects of market access of CGTs. Subsequently, interviews with 16 stakeholders from academia, patient advocacy groups, manufacturers, health insurers, payers, hospital pharmacists, healthcare practitioners, and the Association of Innovative Medicines were conducted. Stakeholders identified challenges and proposed solutions for reimbursement package management, clinical trials, health economics, payment models, and procedural and organisational aspects. Thematic analysis revealed unique country-specific challenges and solutions in the Netherlands. This research provides insights into these challenges and potential solutions, emphasising the need for collaborative efforts among stakeholders to develop practical and multidisciplinary measures to improve the market access landscape for CGTs in the country.

Objectives: The aim of this study is to analyse the trends in technology appraisals for non-small cell lung cancer (NSCLC) treatments performed by the National Institute for Health and Care Excellence (NICE) over the last ten years.

Methods: A systematic search was conducted for single technology appraisals of NSCLC drugs in the online NICE database from 2012 to 2022. Search terms used were ‘non small cell lung cancer’, and ‘NSCLC’. Appraisals that were under development or terminated as well as multiple technology appraisals were considered out of scope.

Results: In the 30 included appraisals for targeted therapies and immunotherapies within NSCLC, a total of 53 different comparators were included by NICE for 41 assorted indications or subgroups. Partitioned survival models were most frequently used, often including three health states and time horizons of up to 30 years. Throughout the decade the use of indirect comparisons was high and became more established and complex over time. Of all appraisals, 90% positively recommended the treatment for use in the UK.

Conclusion: Technology appraisals became more complex over time due to the emergence of targeted therapies and immunotherapies, leading to multiple different indications, subpopulations and comparators that needed to be included in appraisals. Partitioned Survival Analysis (PartSA) models became the cornerstone within NSCLC, with time horizons up to 30 years and over time methods for indirect treatment comparisons became more established. The majority of the appraisals resulted in a positive recommendation for reimbursement.

Aim: The aim of this study was to evaluate the cost-effectiveness of patent foramen ovale (PFO) closure using CARDIOFORM Septal Occluders versus AMPLATZER Septal Occluders, as well as compared to Medical Therapy Alone, from a payor perspective in the United States.

Methods: An economic evaluation compared the value of CARDIOFORM, AMPLATZER, and Medical Therapy Alone. A Markov model simulated a cohort of 1,000 individuals with PFO and a history of cryptogenic stroke, with baseline demographic and clinical characteristics reflecting individuals enrolled in the REDUCE and RESPECT trials over a five-year time horizon. The costs and health consequences associated with complications and adverse events, including recurrent stroke, were compared over a time horizon of 5 years.

Results: PFO closure using CARDIOFORM was economically dominant, providing both cost-savings and improved effectiveness compared to closure with AMPLATZER. It resulted in an estimated savings of over $1.3 million, an additional 24.8 quality-adjusted life-years (QALYs) gained, and 28 strokes avoided in a cohort of 1,000 patients. When compared to Medical Therapy Alone, closure with CARDIOFORM was found to be cost-effective, with an incremental cost-effectiveness ratio (ICER) of$36,697 per QALY gained. Sensitivity and scenario analysis showed the model findings to be highly robust across reasonable changes to baseline input values and assumptions.

Conclusions: The results of this analysis suggest that PFO closure using the CARDIOFORM Septal Occluder is the most cost-effective treatment strategy for patients with a PFO-associated stroke, particularly compared to AMPLATZER where it resulted in both cost-saving and improved patient outcomes.

Background: Poorglycemiccontrolprior to cancer diagnosis for patients with pre-existing type 2 diabetes (T2DM) may predict a worse cancer diagnosis. We investigated the association between pre-diagnosis glycemic control and all-cause mortality in patients with T2DM who develop cancer.

Methods: This prospective cohort study linked data from three sources covering 1989 to 2019: a T2DM benchmarking database, the Netherlands Cancer Registry, and the Personal Records Database. We included patients with T2DM and incident primary breast, colorectal, or prostate cancer (stage 0–III), with target glycemic control defined according to Dutch guidelines. Analysis involved estimating the association between glycemic control and all-cause mortality with Cox proportional hazard models, accounting for individual expected survival relative to the general population and relevant disease (e.g., diabetes duration and medications) and individual (e.g., age and gender) characteristics.

Results: Of the 71,648 linked cases, 620 had breast cancer, 774 had colorectal cancer, and 438 had prostate cancer, with follow-up data available for 6.4 (4.2–8.4), 5.6 (2.7–7.6), and 6.3 (4.5–8.2) years, respectively. Compared with patients with pre-diagnosis glycemic control at target, the HRs and 95% confidence intervals for mortality among those with pre-diagnosis glycemic control not at target were 1.40 (1.00–1.96) for breast cancer, 1.45 (1.12–1.88) for colorectal cancer, and 1.39 (0.98–1.98) for prostate cancer.

Conclusions: Among patients with T2D Min Dutch primary care, poor glycemic control before diagnosis with breast and colorectal cancer can increase mortality compared with good control.

Impact: Glycemic control prior to cancer diagnosis is of prognostic value.

Background: Hyperkinetic movement disorders (HMD) manifest as abnormal and uncontrollable movements. Despite reported involvement of several neural circuits, exact connectivity profiles remain elusive.

Objectives: Providing a comprehensive literature review of resting-state brain connectivity alterations using resting-state fMRI (rs-fMRI). We additionally discuss alterations from the perspective of brain networks, as well as correlations between connectivity and clinical measures.

Methods: A systematic review was performed according to PRISMA guidelines and searching PubMed until October 2022. Rs-fMRI studies addressing ataxia, chorea, dystonia, myoclonus, tics, tremor, and functional movement disorders (FMD) were included. The standardized mean difference was used to summarize findings per region in the Automated Anatomical Labeling atlas for each phenotype. Furthermore, the activation likelihood estimation meta-analytic method was used to analyze convergence of significant between-group differences per phenotype. Finally, we conducted hierarchical cluster analysis to provide additional insights into commonalities and differences across HMD phenotypes.

Results: Most articles concerned tremor (51), followed by dystonia (46), tics (19), chorea (12), myoclonus (11), FMD (11), and ataxia (8). Altered resting-state connectivity was found in several brain regions: in ataxia mainly cerebellar areas; for chorea, the caudate nucleus; for dystonia, sensorimotor and basal ganglia regions; for myoclonus, the thalamus and cingulate cortex; in tics, the basal ganglia, cerebellum, insula, and frontal cortex; for tremor, the cerebello-thalamo-cortical circuit; finally, in FMD, frontal, parietal, and cerebellar regions. Both decreased and increased connectivity were found for all HMD. Significant spatial convergence was found for dystonia, FMD, myoclonus, and tremor. Correlations between clinical measures and resting-state connectivity were frequently described.

Conclusion: Key brain regions contributing to functional connectivity changes across HMD often overlap. Possible increases and decreases of functional connections of a specific region emphasize that HMD should be viewed as a network disorder. Despite the complex interplay of physiological and methodological factors, this review serves to gain insight in brain connectivity profiles across HMD phenotypes.