Trajectories of clinical characteristics, complications and treatment choices in data-driven subgroups of type 2 diabetes.

AIMS/HYPOTHESIS: This study aimed to explore the added value of subgroups that categorise individuals with type 2 diabetes by k-means clustering for two primary care registries (the Netherlands and Scotland), inspired by Ahlqvist's novel diabetes subgroups and previously analysed by Slieker et al. METHODS: We used two Dutch and Scottish diabetes cohorts (N=3054 and 6145; median follow-up=11.2 and 12.3 years, respectively) and defined five subgroups by k-means clustering with age at baseline, BMI, HbA1c, HDL-cholesterol and C-peptide. We investigated differences between subgroups by trajectories of risk factor values (random intercept models), time to diabetes-related complications (logrank tests and Cox models) and medication patterns (multinomial logistic models). We also compared directly using the clustering indicators as predictors of progression vs the k-means discrete subgroups. Cluster consistency over follow-up was assessed. RESULTS: Subgroups' risk factors were significantly different, and these differences remained generally consistent over follow-up. Among all subgroups, individuals with severe insulin resistance faced a significantly higher risk of myocardial infarction both before (HR 1.65; 95% CI 1.40, 1.94) and after adjusting for age effect (HR 1.72; 95% CI 1.46, 2.02) compared with mild diabetes with high HDL-cholesterol. Individuals with severe insulin-deficient diabetes were most intensively treated, with more than 25% prescribed insulin at 10 years of diagnosis. For severe insulin-deficient diabetes relative to mild diabetes, the relative risks for using insulin relative to no common treatment would be expected to increase by a factor of 3.07 (95% CI 2.73, 3.44), holding other factors constant. Clustering indicators were better predictors of progression variation relative to subgroups, but prediction accuracy may improve after combining both. Clusters were consistent over 8 years with an accuracy ranging from 59% to 72%. CONCLUSIONS/INTERPRETATION: Data-driven subgroup allocations were generally consistent over follow-up and captured significant differences in risk factor trajectories, medication patterns and complication risks. Subgroups serve better as a complement rather than as a basis for compressing clustering indicators.

A Blueprint for Multi-use Disease Modeling in Health Economics: Results from Two Expert-Panel Consultations.

BACKGROUND: The current use of health economic decision models in HTA is mostly confined to single use cases, which may be inefficient and result in little consistency over different treatment comparisons, and consequently inconsistent health policy decisions, for the same disorder. Multi-use disease models (MUDMs) (other terms: generic models, whole disease models, disease models) may offer a solution. However, much is uncertain about their definition and application. The current research aimed to develop a blueprint for the application of MUDMs. METHODS: We elicited expert opinion using a two-round modified Delphi process. The panel consisted of experts and stakeholders in health economic modelling from various professional backgrounds. The first questionnaire concerned definition, terminology, potential applications, issues and recommendations for MUDMs and was based on an exploratory scoping review. In the second round, the panel members were asked to reconsider their input, based on feedback regarding first-round results, and to score issues and recommendations for priority. Finally, adding input from external advisors and policy makers in a structured way, an overview of issues and challenges was developed during two team consensus meetings. RESULTS: In total, 54 respondents contributed to the panel results. The term 'multi-use disease models' was proposed and agreed upon, and a definition was provided. The panel prioritized 10 potential applications (with comparing alternative policies and supporting resource allocation decisions as the top 2), while 20 issues (with model transparency and stakeholders' roles as the top 2) were identified as challenges. Opinions on potential features concerning operationalization of multi-use models were given, with 11 of these subsequently receiving high priority scores (regular updates and revalidation after updates were the top 2). CONCLUSIONS: MUDMs would improve on current decision support regarding cost-effectiveness information. Given feasibility challenges, this would be most relevant for diseases with multiple treatments, large burden of disease and requiring more complex models. The current overview offers policy makers a starting point to organize the development, use, and maintenance of MUDMs and to support choices concerning which diseases and policy decisions they will be helpful for.

A Model of Individual BMI Trajectories.

A risk factor model of body mass index (BMI) is an important building block of health simulations aimed at estimating government policy effects with regard to overweight and obesity. We created a model that generates representative population level distributions and that also mimics realistic BMI trajectories at an individual level so that policies aimed at individuals can be simulated. The model is constructed by combining several datasets. First, the population level distribution is extracted from a large, cross-sectional dataset. The trend in this distribution is estimated from historical data. In addition, longitudinal data are used to model how individuals move along typical trajectories over time. The model faithfully describes the population level distribution of BMI, stratified by sex, level of education and age. It is able to generate life course trajectories for individuals which seem plausible, but it does not capture extreme fluctuations, such as rapid weight loss.

Cost-Effectiveness of SGLT2 Inhibitors in a Real-World Population: A MICADO Model-Based Analysis Using Routine Data from a GP Registry.

OBJECTIVE: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to reduce the risk of cardiovascular complications, which largely drive diabetes' health and economic burdens. Trial results indicated that SGLT2i are cost effective. However, these findings may not be generalizable to the real-world target population. This study aims to evaluate the cost effectiveness of SGLT2i in a routine care type 2 diabetes population that meets Dutch reimbursement criteria using the MICADO model. METHODS: Individuals from the Hoorn Diabetes Care System cohort (N = 15,392) were filtered to satisfy trial inclusion criteria (including EMPA-REG, CANVAS, and DECLARE-TIMI58) or satisfy the current Dutch reimbursement criteria for SGLT2i. We validated a health economic model (MICADO) by comparing simulated and observed outcomes regarding the relative risks of events in the intervention and comparator arm from three trials, and used the validated model to evaluate the long-term health outcomes using the filtered cohorts' baseline characteristics and treatment effects from trials and a review of observational studies. The incremental cost-effectiveness ratio (ICER) of SGLT2i, compared with care-as-usual, was assessed from a third-party payer perspective, measured in euros (2021 price level), using a discount rate of 4% for costs and 1.5% for effects. RESULTS: From Dutch individuals with diabetes in routine care, 15.8% qualify for the current Dutch reimbursement criteria for SGLT2i. Their characteristics were significantly different (lower HbA1c, higher age, and generally more preexisting complications) than trial populations. After validating the MICADO model, we found that lifetime ICERs of SGLT2i, when compared with usual care, were favorable (< €20,000/QALY) for all filtered cohorts, resulting in an ICER of €5440/QALY using trial-based treatment effect estimates in reimbursed population. Several pragmatic scenarios were tested, the ICERs remained favorable. CONCLUSIONS: Although the Dutch reimbursement indications led to a target group that deviates from trial populations, SGLT2i are likely to be cost effective when compared with usual care.

Potential Value of Identifying Type 2 Diabetes Subgroups for Guiding Intensive Treatment: A Comparison of Novel Data-Driven Clustering With Risk-Driven Subgroups.

OBJECTIVE: To estimate the impact on lifetime health and economic outcomes of different methods of stratifying individuals with type 2 diabetes, followed by guideline-based treatment intensification targeting BMI and LDL in addition to HbA1c. RESEARCH DESIGN AND METHODS: We divided 2,935 newly diagnosed individuals from the Hoorn Diabetes Care System (DCS) cohort into five Risk Assessment and Progression of Diabetes (RHAPSODY) data-driven clustering subgroups (based on age, BMI, HbA1c, C-peptide, and HDL) and four risk-driven subgroups by using fixed cutoffs for HbA1c and risk of cardiovascular disease based on guidelines. The UK Prospective Diabetes Study Outcomes Model 2 estimated discounted expected lifetime complication costs and quality-adjusted life-years (QALYs) for each subgroup and across all individuals. Gains from treatment intensification were compared with care as usual as observed in DCS. A sensitivity analysis was conducted based on Ahlqvist subgroups. RESULTS: Under care as usual, prognosis in the RHAPSODY data-driven subgroups ranged from 7.9 to 12.6 QALYs. Prognosis in the risk-driven subgroups ranged from 6.8 to 12.0 QALYs. Compared with homogenous type 2 diabetes, treatment for individuals in the high-risk subgroups could cost 22.0% and 25.3% more and still be cost effective for data-driven and risk-driven subgroups, respectively. Targeting BMI and LDL in addition to HbA1c might deliver up to 10-fold increases in QALYs gained. CONCLUSIONS: Risk-driven subgroups better discriminated prognosis. Both stratification methods supported stratified treatment intensification, with the risk-driven subgroups being somewhat better in identifying individuals with the most potential to benefit from intensive treatment. Irrespective of stratification approach, better cholesterol and weight control showed substantial potential for health gains.

Prediction of complications in health economic models of type 2 diabetes: a review of methods used.

AIM: Diabetes health economic (HE) models play important roles in decision making. For most HE models of diabetes 2 diabetes (T2D), the core model concerns the prediction of complications. However, reviews of HE models pay little attention to the incorporation of prediction models. The objective of the current review is to investigate how prediction models have been incorporated into HE models of T2D and to identify challenges and possible solutions. METHODS: PubMed, Web of Science, Embase, and Cochrane were searched from January 1, 1997, to November 15, 2022, to identify published HE models for T2D. All models that participated in The Mount Hood Diabetes Simulation Modeling Database or previous challenges were manually searched. Data extraction was performed by two independent authors. Characteristics of HE models, their underlying prediction models, and methods of incorporating prediction models were investigated. RESULTS: The scoping review identified 34 HE models, including a continuous-time object-oriented model (n = 1), discrete-time state transition models (n = 18), and discrete-time discrete event simulation models (n = 15). Published prediction models were often applied to simulate complication risks, such as the UKPDS (n = 20), Framingham (n = 7), BRAVO (n = 2), NDR (n = 2), and RECODe (n = 2). Four methods were identified to combine interdependent prediction models for different complications, including random order evaluation (n = 12), simultaneous evaluation (n = 4), the 'sunflower method' (n = 3), and pre-defined order (n = 1). The remaining studies did not consider interdependency or reported unclearly. CONCLUSIONS: The methodology of integrating prediction models in HE models requires further attention, especially regarding how prediction models are selected, adjusted, and ordered.

Physical and mental health outcomes of COVID-19 induced delay in oncological care: A systematic review.

Background: During the COVID-19 pandemic cancer patients might have experienced delays in screening, diagnosis and/or treatment. A systematic review was conducted to give an overview of the effects of COVID-19 induced delays in oncological care on the physical and mental health outcomes of cancer patients. Methods: MEDLINE and EMBASE databases were searched for articles on the effects of COVID-19 induced delays on physical and mental health outcomes. Results: Out of 1333 papers, eighteen observational, and twelve modelling studies were included. In approximately half of the studies, tumor stage distribution differed during the pandemic compared to before the pandemic. Modelling studies predicted that the estimated increase in the number of deaths ranged from -0.04 to 30%, and the estimated reduction in survival ranged from 0.4 to 35%. Varying results on the impact on mental health, e.g. anxiety and depression, were seen. Conclusions: Due to large methodological discrepancies between the studies and the varying results, the effect of COVID-19 induced delays on the physical and mental health outcomes of cancer patients remains uncertain. While modelling studies estimated an increase in mortality, observational studies suggest that mortality might not increase to a large extent. More longitudinal observational data from the pandemic period is needed for more conclusive results.

Estimating the health impact of delayed elective care during the COVID -19 pandemic in the Netherlands.

BACKGROUND: The COVID-19 pandemic had a major impact on the continuity of healthcare provision. Appointments, treatments and surgeries for non-COVID patients were often delayed, with associated health losses for patients involved. OBJECTIVE: To develop a method to quantify the health impact of delayed elective care for non-COVID patients. METHODS: A model was developed that estimated the backlog of surgical procedures in 2020 and 2021 using hospital registry data. Quality-adjusted life years (QALYs) were obtained from the literature to estimate the non-generated QALYs related to the backlog. In sensitivity analyses QALY values were varied by type of patient prioritization. Scenario analyses for future increased surgical capacity were performed. RESULTS: In 2020 and 2021 an estimated total of 305,374 elective surgeries were delayed. These delays corresponded with 319,483 non-generated QALYs. In sensitivity analyses where QALYs varied by type of patient prioritization, non-generated QALYs amounted to 150,973 and 488,195 QALYs respectively. In scenario analyses for future increased surgical capacity in 2022-2026, the non-generated QALYs decreased to 311,220 (2% future capacity increase per year) and 300,710 (5% future capacity increase per year). Large differences exist in the extent to which different treatments contributed to the total health losses. CONCLUSIONS: The method sheds light on the indirect harm related to the COVID-19 pandemic. The results can be used for policy evaluations of COVID-19 responses, in preparations for future waves or other pandemics and in prioritizing the allocation of resources for capacity increases.

BMI trajectories after primary school-based lifestyle intervention: Unravelling an uncertain future. A mixed methods study.

This mixed methods study aimed to examine plausible body mass index (BMI) trajectories after exposure to a primary school-based lifestyle intervention to aid in estimating the long-term intervention benefits. BMI trajectories for children at control schools (mean 7.6 years of age) were modelled until 20 years of age through extrapolating trial evidence (N = 1647). A reference scenario assumed that the observed 2-year effects of the 'Healthy Primary Schools of the Future' (HPSF) and 'Physical Activity Schools' (PAS) were fully maintained over time. This was modelled by applying the observed 2-year BMI effects until 20 years of age. Expert opinions on likely trends in effect maintenance after the 2-year intervention period were elicited qualitatively and quantitatively, and were used for developing alternative scenarios. Expert elicitation revealed three scenarios: (a) a constant exposure-effect and an uncontrolled environment with effect decay scenario, (b) a household multiplier and an uncontrolled environment with effect decay scenario, and (c) a household multiplier and maintainer scenario. The relative effect of HPSF at 20 years of age was -0.21 kg/m2 under the reference scenario, and varied from -0.04 kg/m2 (a) to -0.06 kg/m2 (b), and -0.50 kg/m2 (c). For PAS, the relative effect was -0.17 kg/m2 under the reference scenario, and varied from -0.04 kg/m2 (a, b), to -0.21 kg/m2 (c). The mixed methods approach proved to be useful in modelling plausible BMI trajectories and specifying uncertainty on effect maintenance. Further observations until adulthood could reduce the uncertainty around future benefits. This trial was retrospectively registered at Clinicaltrials.gov (NCT02800616).

Lifetime cost-effectiveness and equity impacts of the Healthy Primary School of the Future initiative.

BACKGROUND: This study estimated the lifetime cost-effectiveness and equity impacts associated with two lifestyle interventions in the Dutch primary school setting (targeting 4-12 year olds). METHODS: The Healthy Primary School of the Future (HPSF; a healthy school lunch and structured physical activity) and the Physical Activity School (PAS; structured physical activity) were compared to the regular Dutch curriculum (N = 1676). An adolescence model, calculating weight development, and the RIVM Chronic Disease Model, calculating overweight-related chronic diseases, were linked to estimate the lifetime impact on chronic diseases, quality adjusted life years (QALYs), healthcare, and productivity costs. Cost-effectiveness was expressed as the additional costs/QALY gained and we used €20,000 as threshold. Scenario analyses accounted for alternative effect maintenance scenarios and equity analyses examined cost-effectiveness in different socioeconomic status (SES) groups. RESULTS: HPSF resulted in a lifetime costs of €773 (societal perspective) and a lifetime QALY gain of 0.039 per child versus control schools. HPSF led to lower costs and more QALYs as compared to PAS. From a societal perspective, HPSF had a cost/QALY gained of €19,734 versus control schools, 50% probability of being cost-effective, and beneficial equity impact (0.02 QALYs gained/child for low versus high SES). The cost-effectiveness threshold was surpassed when intervention effects decayed over time. CONCLUSIONS: HPSF may be a cost-effective and equitable strategy for combatting the lifetime burden of unhealthy lifestyles. The win-win situation will, however, only be realised if the intervention effect is sustained into adulthood for all SES groups. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT02800616 ). Registered 15 June 2016 - Retrospectively registered.

Cost-effectiveness of inactivated influenza vaccination in children with medical risk conditions in the Netherlands.

BACKGROUND: In many countries, annual immunization with inactivated influenza vaccine (IIV) is recommended for children with medical risk conditions. Prior cost-effectiveness analyses found such immunization to be cost saving, but assumed effectiveness against non-severe influenza outcomes and a higher effectiveness against severe influenza outcomes than recent studies would suggest. However, recent vaccine studies do not indicate any reduction in community or outpatient disease episodes in IIV immunized individuals. We therefore evaluated cost-effectiveness of IIV immunization in children with medical risk conditions in the Netherlands, assuming that IIV reduces influenza-related hospitalization and death, but has no meaningful impact on non-severe health outcomes. METHODS: A health economic decision tree model was developed to evaluate health effects and costs of annual IIV immunization versus no immunization. Model inputs were based on our study on influenza-related primary care visits and other literature. Immunization was considered cost effective if associated costs were less than €20,000 per quality-adjusted life year (QALY) gained. Probabilistic sensitivity analyses were performed to assess robustness of results, and one-way sensitivity analyses and scenario analyses were done to assess the influence of individual parameters. RESULTS: Annual IIV prevents an average of 1.59 influenza-related hospitalizations and 0.02 deaths per 1,000 children with medical risk conditions. This results in an expected QALY gain of 0.43 at incremental costs of €21,564 per 1,000 children, corresponding to an incremental cost-effectiveness ratio (ICER) of €50,297/QALY compared to no immunization. Under base case assumptions, immunization had a 5% probability of being cost effective. Results were most influenced by vaccine efficacy against fatal influenza, QALY loss due to death, and mortality rate. CONCLUSIONS: If IIV only reduces severe disease outcomes, as current evidence suggests, annual immunization of medical risk children is unlikely to be cost effective. Results should however be interpreted with caution as cost-effectiveness is largely dependent on incidence and QALY losses for fatal influenza, for which evidence is scarce.

Cost-effectiveness analysis of a GP- and parent-directed intervention to reduce antibiotic prescribing for children with respiratory tract infections in primary care.

OBJECTIVES: We evaluated costs and effects of the RAAK (RAtional Antibiotic use Kids) intervention (GP online training and information booklets for parents), aiming to reduce antibiotic prescribing for children with respiratory tract infection (RTI). METHODS: We conducted a trial-based cost-effectiveness analysis from a societal perspective. We included children consulting the GP with RTI for whom parents kept a 2 week (cost) diary. The antibiotic prescribing rate was the percentage of children receiving an antibiotic prescription at the index consultation and during the 2 weeks of follow-up. The cost difference between the intervention and usual care groups per percentage decrease in antibiotic prescribing was calculated. Bootstrapping was used to assess uncertainty surrounding the outcomes. RESULTS: Costs and effects of 153 children in the intervention group and 107 children in the usual care group were available for analysis. Antibiotic prescribing was 12% lower in the intervention group and costs were €10.27 higher in the intervention group compared with the usual care group. This resulted in an incremental cost-effectiveness ratio of €0.85 per percentage decrease in antibiotic prescribing. The probability that the intervention was more effective, but more expensive, was 53%, whereas the probability that the intervention was more effective and less expensive compared with usual care was 41%. CONCLUSIONS: The online training for GPs and the information booklet for parents resulted in a decrease in antibiotic prescribing in children with RTI, at very low cost, and should therefore be considered for implementation in primary care.

Ixekizumab for Treating Moderate-to-Severe Plaque Psoriasis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence invited Eli Lilly and Company Ltd, the company manufacturing ixekizumab (tradename Taltz®), to submit evidence for the clinical and cost effectiveness of ixekizumab. Ixekizumab was compared with tumour necrosis factor-α inhibitors (etanercept, infliximab, adalimumab), ustekinumab, secukinumab, best supportive care and, if non-biological treatment or phototherapy is suitable, also compared with systemic non-biological therapies and phototherapy with ultraviolet B radiation for adults with moderate-to-severe plaque psoriasis. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Center, was commissioned as the independent Evidence Review Group. This article presents a summary of the company submission, the Evidence Review Group report and the development of the National Institute for Health and Care Excellence guidance for the use of this drug in England and Wales by the Appraisal Committee. The Evidence Review Group produced a critical review of the clinical and cost effectiveness of ixekizumab based on the company submission. The company submission presented three randomised controlled trials identified in a systematic review. All randomised controlled trials were phase III, multicentre placebo-controlled trials including 3866 participants with moderate-to-severe psoriasis. Two trials also included an active comparator (etanercept). All randomised controlled trials showed statistically significant increases in two primary outcomes, static Physician Global Assessment (0,1) and improvement of 75% from baseline in the Psoriasis Area and Severity Index. Ixekizumab was generally well tolerated in the randomised controlled trials, with similar discontinuation rates because of adverse events as placebo or etanercept. The most frequent adverse events of special interest were infections and injection-site reactions. The company submission also included a network meta-analysis of relevant comparators. The Evidence Review Group highlighted some issues regarding the systematic review process and an issue with the generalisability of the findings in that the trials failed to include patients with moderate psoriasis according to a widely used definition. This issue was considered by the Appraisal Committee and the population was deemed generalisable to patients in England and Wales. Based on the network meta-analysis, the Appraisal Committee concluded that ixekizumab was more clinically effective than adalimumab and ustekinumab, and agreed it was likely that ixekizumab was similarly effective compared with secukinumab and infliximab while tolerability was similar to other biological treatments approved for treating psoriasis. The Evidence Review Group's critical assessment of the company's economic evaluation highlighted a number of concerns, including (1) the use of relative outcomes such as Psoriasis Area and Severity Index response to model the cost effectiveness; (2) the exclusion of the consequences of adverse events; (3) the assumption of no utility gain in the induction phase; (4) equal annual discontinuation rates for all treatments; (5) the selection of treatment sequences for consideration in the analyses and; (6) the transparency of the Visual Basic for Applications code used to develop the model. Although some of these issues were adjusted in the Evidence Review Group base case, the Evidence Review Group could not estimate the impact of all of these issues, and thus acknowledges that there are still uncertainties concerning the cost-effectiveness evidence. In the Evidence Review Group base-case incremental analysis, the treatment sequence incorporating ixekizumab in the second line has an incremental cost-effectiveness ratio of £25,532 per quality-adjusted life-year gained vs. the etanercept sequence. Ixekizumab in the first-line sequence has an incremental cost-effectiveness ratio of £39,129 per quality-adjusted life-year gained compared with the treatment sequence incorporating ixekizumab in the second line. Consistent with its conclusion regarding clinical effectiveness, the Appraisal Committee concluded that the cost effectiveness of ixekizumab for treating moderate-to-severe plaque psoriasis was similar to that of other biological treatments, already recommended in previous National Institute for Health and Care Excellence guidance. The committee concluded that the incremental cost-effectiveness ratio was within the range that could be considered a cost-effective use of National Health Service resources.

Ticagrelor for Secondary Prevention of Atherothrombotic Events After Myocardial Infarction: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited AstraZeneca, the manufacturer of ticagrelor (Brilique®), to submit evidence on the clinical and cost effectiveness of ticagrelor 60 mg twice daily (BID) in combination with low-dose aspirin [acetylsalicylic acid (ASA)] compared with ASA only for secondary prevention of atherothrombotic events in patients with a history of myocardial infarction (MI) and who are at increased risk of atherothrombotic events. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Centre+, was commissioned as the evidence review group (ERG). This paper summarises the company submission (CS), the ERG report and the NICE guidance produced by the appraisal committee (AC) for the use of ticagrelor in England and Wales. The ERG critically reviewed the clinical- and cost-effectiveness evidence in the CS. The systematic review conducted as part of the CS identified one randomised controlled trial (RCT), PEGASUS-TIMI 54. This trial reported the time to first occurrence of any event from the composite of cardiovascular death, MI and stroke as the primary outcome (hazard ratio 0.84 ticagrelor 60 mg BID vs. placebo, 95% confidence interval 0.74-0.95). The population addressed in the CS was a subgroup of the PEGASUS-TIMI 54 trial population, i.e. the 'base-case' population, which comprised patients who had experienced an MI between 1 and 2 years ago, whereas the full trial population included patients who had experienced an MI between 1 and 3 years ago. While the ERG believed the findings of this RCT to be robust, doubts concerning the applicability of the trial to UK patients were raised. The company submitted an individual patient simulation model to estimate the cost-effectiveness of ticagrelor 60 mg BID + ASA versus ASA only. Parametric time-to-event models were used to estimate the time to first and subsequent (cardiovascular) events, time to treatment discontinuation and time to adverse events. The company's base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of £20,098 per quality-adjusted life-year (QALY) gained. The main issues surrounding the cost effectiveness of ticagrelor 60 mg BID + ASA were the use of parametric time-to-event models estimated based on the full trial population instead of being fitted to the 'label' population (the 'label' population comprised the 'base-case' population and patients who started ticagrelor 60 mg BID within 1 year of previous adenosine diphosphate inhibitor treatment), the incorrect implementation of the probabilistic sensitivity analysis (PSA) of the individual patient simulation, and simplifications of the model structure that may have biased the health benefits and costs estimations of the intervention and comparator. The ERG believed the use of the full trial population to inform the parametric time-to-event models was not appropriate because the 'label' population was the main focus of the scope and CS. The ERG could not investigate the magnitude of the bias introduced by this assumption. The PSA of the individual patient simulation provided unreliable probabilistic results and underestimated the uncertainty surrounding the results because it was based on a single patient. The ERG used the cohort simulation presented in the cost-effectiveness model to perform its base-case and additional analyses and to obtain probabilistic results. The ERG amended the company cost-effectiveness model, which resulted in an ERG base-case ICER of £24,711 per QALY gained. In its final guidance, the AC recommended treatment with ticagrelor 60 mg BID + low-dose ASA for secondary prevention of atherothrombotic events in adults who have had an MI and are at increased risk of atherothrombotic events.

Trifluridine-Tipiracil for Previously Treated Metastatic Colorectal Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited Servier, the company manufacturing trifluridine and tipiracil (T/T; trade name: Lonsurf®), to submit evidence for the clinical and cost effectiveness of T/T compared with best supportive care (BSC) for metastatic colorectal cancer (third-line or later). Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Center, was commissioned as the Evidence Review Group (ERG). This paper presents a summary of the company's submission (CS), the ERG report and the development of the NICE guidance for the use of this drug in England and Wales by the appraisal committee (AC). The ERG produced a critical review of the clinical and cost effectiveness of T/T based upon the CS. In the CS, pooled evidence of two trials (a phase II trial and RECOURSE) showed that T/T resulted in a significant increase in overall survival [OS; hazard ratio (HR) 0.67, 95% CI 0.58-0.78] and progression-free survival (PFS; HR 0.46, 95% CI 0.40-0.53). The AC considered the survival benefit of T/T clinically meaningful although relatively small. The ERG highlighted that none of the participants in the phase II trial and approximately half of the RECOURSE participants (394 of 800) were from Europe, which might limit the applicability of the study findings to the NHS. Moreover, the ERG's critical assessment of the company's economic evaluation highlighted a number of concerns that resulted in 11 adjustments to the company's base-case analysis. The ERG adjustments that had the largest impact were using the RECOURSE trial data only (instead of the pooled evidence), fixing errors and violations and using the utilities from the CORRECT trial (identified in the literature review) only. The ERG preferred to use the RECOURSE trial data only given the suboptimal methodology used by the company to pool the evidence. However, since there were no fundamental arguments to prevent the two trials from being pooled, the ERG also presented its base-case analysis based on the pooled effectiveness estimates. The company base-case resulted in an incremental cost effectiveness ratio (ICER) of £44,032 per QALY gained while the ERG base-case resulted in ICERs of £52,695 and £49,392 per QALY gained based on the RECOURSE trial only and pooled evidence, respectively. Since the AC concluded that the most plausible ICER was £49,392 per QALY gained, and that T/T meets end-of-life criteria, T/T was recommended as a cost effective use of NHS resources.

An alternative approach identified optimal risk thresholds for treatment indication: an illustration in coronary heart disease.

OBJECTIVES: Treatment thresholds based on risk predictions can be optimized by considering various health (economic) outcomes and performing marginal analyses, but this is rarely performed. We demonstrate a general approach to identify treatment thresholds optimizing individual health (economic) outcomes, illustrated for statin treatment based on 10-year coronary heart disease (CHD) risk predicted by the Framingham risk score. STUDY DESIGN AND SETTING: Creating a health economic model for a risk-based prevention strategy, risk thresholds can be evaluated on several outcomes of interest. Selecting an appropriate threshold range and decrement size for the thresholds and adapting the health economic model accordingly, outcomes can be calculated for each risk threshold. A stepwise, or marginal, comparison of clinical as well as health economic outcomes, that is, comparing outcomes using a specific threshold to outcomes of the former threshold while gradually lowering the threshold, then takes into account the balance between additional numbers of individuals treated and their outcomes (additional health effects and costs). In our illustration, using a Markov model for CHD, we evaluated risk thresholds by gradually lowering thresholds from 20% to 0%. RESULTS: This approach can be applied to identify optimal risk thresholds on any outcome, such as to limit complications, maximize health outcomes, or optimize cost-effectiveness. In our illustration, keeping the population-level fraction of statin-induced complications <10% resulted in thresholds of T = 6% (men) and T = 2% (women). Lowering the threshold and comparing quality-adjusted life-years (QALYs) after each 1% decrease, QALYs were gained down to T = 1% (men) and T = 0% (women). Also accounting for costs, net health benefits were favorable down to T = 3% (men) and T = 6% (women). CONCLUSION: Using a stepwise risk-based approach to threshold optimization allows for preventive strategies that optimize outcomes. Presenting this comprehensive overview of outcomes will better inform decision makers when defining a treatment threshold.

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.

Linking the Regulatory and Reimbursement Processes for Medical Devices: The Need for Integrated Assessments.

Much criticism has been directed at the licencing requirements for medical devices (MDs) as they often result in a lack of robust evidence to inform health technology assessment (HTA) decisions. To better understand the current international decisional framework on MD technologies, we undertook three linked research studies: a review of the device regulatory procedures, a survey of current HTA practices and an empirical comparison of HTA reports of drugs versus MDs. Our review confirms that current device regulatory processes across the globe are substantially less stringent than drugs. As a result, international HTA agencies report that they face a number of challenges when assessing MDs, including reliance on suboptimal data to make clinical and cost-effectiveness decisions. Whilst many HTA agencies have adapted their processes and procedures to handle MD technology submissions, in our comparison of HTA reports we found little evidence of the application of methodologies that take account of device-specific issues, such as incremental development. Overall, our research reinforces the need for better linkage between licencing and HTA and the development and application of innovative HTA methodologies with the objective of securing faster patient access for those technologies that can be shown to represent good value for money. © 2017 The Authors. Health Economics Published by John Wiley & Sons, Ltd.

Cost-effectiveness of screening strategies to detect heart failure in patients with type 2 diabetes.

BACKGROUND: Heart failure (HF), especially with preserved ejection fraction (HFpEF) is common in older patients with type 2 diabetes (T2DM), but often not recognized. Early HF detection in older T2DM patients may be worthwhile because treatment may be initiated in an early stage, with clear beneficial treatment in those with reduced ejection fraction (HFrEF), but without clear prognostic beneficial treatment in those with HFpEF. Because both types of HF may be uncovered in older T2DM, screening may improve health outcomes at acceptable costs. We assessed the cost-effectiveness of five screening strategies in patients with T2DM aged 60 years or over. METHODS: We built a Markov model with a lifetime horizon based on the prognostic results from our screening study of 581 patients with T2DM, extended with evidence from literature. Cost-effectiveness was calculated from a Dutch healthcare perspective as additional costs (Euros) per additional quality-adjusted life-year (QALY) gained. We performed probabilistic sensitivity analysis to assess robustness of these outcomes. Scenario analyses were performed to assess the influence of the availability of effective treatment of heart failure with preserved ejection fraction. RESULTS: For willingness to pay values in the range of €6050/QALY-€31,000/QALY for men and €6300/QALY-€42,000/QALY for women, screening-based checking the electronic medical record for patient characteristics and medical history plus the assessment of symptoms had the highest probability of being cost-effective. For higher willingness-to-pay values, direct echocardiography was the preferred screening strategy. Cost-effectiveness of all screening strategies improved with the increase in effectiveness of treatment for HFpEF. CONCLUSIONS: Screening for HF in older community-dwelling patients with T2DM is cost-effective at the commonly used willingness-to-pay threshold of €20.000/QALY by checking the electronic medical record for patient characteristics and medical history plus the assessment of symptoms. The simplicity of such a strategy makes it feasible for implementation in existing primary care diabetes management programs.