Mapping EQ-5D-3L to EQ-5D-5L.

OBJECTIVES: The original 3-level EQ-5D (EQ-5D-3L) includes 5 dimensions with 3 levels of problems per dimension. Since 2010, a more sensitive version with 5 levels of problems per dimension (EQ-5D-5L) has become available. Population value sets have been developed for both versions of the questionnaire. The objective of this research was to develop a mapping function to link EQ-5D-3L responses to value sets for the EQ-5D-5L. METHODS: Various algorithms were developed to link EQ-5D-3L and EQ-5D-5L responses using data from an observational study including members of 10 subgroups (N = 3580) who completed both versions of the questionnaire. Nonparametric and ordinal logistic regression models were fit to the data and compared using Akaike's information criterion (AIC) as well as the mean absolute error and root mean squared error of predictions. Results were contrasted qualitatively and quantitatively with those of an alternative copula-based approach. RESULTS: Including indicants of problems for other EQ-5D-3L dimensions as regressors in the modeling yielded the greatest improvement in prediction accuracy. Adding age and gender lowered the AIC without improving predictions, while including a latent factor lowered the AIC further and slightly improved predictive accuracy. Models that conditioned on problems in other EQ-5D-3L dimensions yielded more accurate predictions than the alternative copula-based approach in subgroups defined by age and gender. CONCLUSION: We present novel algorithms to map EQ-5D-3L responses to EQ-5D-5L value sets. The recommended approach is based on an ordinal logistic regression that disregards age and gender and accounts for unobserved heterogeneity using a latent factor.

Cost-effectiveness of additional blood screening tests in the Netherlands.

BACKGROUND: During the past decade, blood screening tests such as triplex nucleic acid amplification testing (NAT) and human T-cell lymphotropic virus type I or I (HTLV-I/II) antibody testing were added to existing serologic testing for hepatitis B virus (HBV), human immunodeficiency virus (HIV), and hepatitis C virus (HCV). In some low-prevalence regions these additional tests yielded disputable benefits that can be valuated by cost-effectiveness analyses (CEAs). CEAs are used to support decision making on implementation of medical technology. We present CEAs of selected additional screening tests that are not uniformly implemented in the EU. STUDY DESIGN AND METHODS: Cost-effectiveness was analyzed of: 1) HBV, HCV, and HIV triplex NAT in addition to serologic testing; 2) HTLV-I/II antibody test for all donors, for first-time donors only, and for pediatric recipients only; and 3) hepatitis A virus (HAV) for all donations. Disease progression of the studied viral infections was described in five Markov models. RESULTS: In the Netherlands, the incremental cost-effectiveness ratio (ICER) of triplex NAT is €5.20 million per quality-adjusted life-year (QALY) for testing minipools of six donation samples and €4.65 million/QALY for individual donation testing. The ICER for anti-HTLV-I/II is €45.2 million/QALY if testing all donations, €2.23 million/QALY if testing new donors only, and €27.0 million/QALY if testing blood products for pediatric patients only. The ICER of HAV NAT is €18.6 million/QALY. CONCLUSION: The resulting ICERs are very high, especially when compared to other health care interventions. Nevertheless, these screening tests are implemented in the Netherlands and elsewhere. Policy makers should reflect more explicit on the acceptability of costs and effects whenever additional blood screening tests are implemented.

An Innovative Approach to Modelling the Optimal Treatment Sequence for Patients with Relapsing-Remitting Multiple Sclerosis: Implementation, Validation, and Impact of the Decision-Making Approach.

INTRODUCTION: An innovative computational model was developed to address challenges regarding the evaluation of treatment sequences in patients with relapsing-remitting multiple sclerosis (RRMS) through the concept of a 'virtual' physician who observes and assesses patients over time. We describe the implementation and validation of the model, then apply this framework as a case study to determine the impact of different decision-making approaches on the optimal sequence of disease-modifying therapies (DMTs) and associated outcomes. METHODS: A patient-level discrete event simulation (DES) was used to model heterogeneity in disease trajectories and outcomes. The evaluation of DMT options was implemented through a Markov model representing the patient's disease; outcomes included lifetime costs and quality of life. The DES and Markov models underwent internal and external validation. Analyses of the optimal treatment sequence for each patient were based on several decision-making criteria. These treatment sequences were compared to current treatment guidelines. RESULTS: Internal validation indicated that model outcomes for natural history were consistent with the input parameters used to inform the model. Costs and quality of life outcomes were successfully validated against published reference models. Whereas each decision-making criterion generated a different optimal treatment sequence, cladribine tablets were the only DMT common to all treatment sequences. By choosing treatments on the basis of minimising disease progression or number of relapses, it was possible to improve on current treatment guidelines; however, these treatment sequences were more costly. Maximising cost-effectiveness resulted in the lowest costs but was also associated with the worst outcomes. CONCLUSIONS: The model was robust in generating outcomes consistent with published models and studies. It was also able to identify optimal treatment sequences based on different decision criteria. This innovative modelling framework has the potential to simulate individual patient trajectories in the current treatment landscape and may be useful for treatment switching and treatment positioning decisions in RRMS.

A modeling approach to evaluate long-term outcome of prophylactic and on demand treatment strategies for severe hemophilia A.

BACKGROUND: Severe hemophilia requires life-long treatment with expensive clotting factor concentrates; studies comparing effects of different therapeutic strategies over decades are very difficult to perform. A simulation model was developed to evaluate the long-term outcome of on demand, prophylactic and mixed treatment strategies for patients with severe hemophilia A. DESIGN AND METHODS: A computer model was developed based on individual patients' data from a Dutch cohort study in which intermediate dose prophylaxis was used and a French cohort study in which on demand treatment was used, and multivariate regression analyses. This model simulated individual patients' life expectancy, onset of bleeding, life-time joint bleeds, radiological outcome and concentrate use according to the different treatment strategies. RESULTS: According to the model, life-time on demand treatment would result in an average of 1,494 joint bleeds during the hemophiliac's life, and consumption of 4.9 million IU of factor VIII concentrate. In contrast, life-time intermediate dose prophylaxis resulted in a mean of 357 joint bleeds and factor consumption of 8.3 million IU. A multiple switch strategy (between prophylactic and on demand treatment based on bleeding pattern) resulted in a mean number of 395 joint bleeds and factor consumption of 6.6 million IU. The estimated proportion of patients with Pettersson scores over 28 points was 32% for both the prophylactic and the multiple switching strategies, compared to 76% for continuous on demand treatment. CONCLUSIONS: The present model allows evaluation of the impact of various treatment strategies on patients' joint bleeds and clotting factor consumption. It may be expanded with additional data to allow more precise estimates and include economic evaluations of treatment strategies.

Cross-sectional study into the costs and impact on family functioning of 4-year-old children with aggressive behavior.

Early-onset aggressive behavior is known for its negative developmental consequences, and the associated high costs for families, the health care system and wider society. Although the origins of aggressive behavior are to be found in early childhood, the costs incurred by aggressive behavior of young children have not been studied extensively. The present study aimed to investigate whether preschool children with a high level of aggressive behavior already differ in the generated amount of costs and impact on family functioning from children with lower levels of aggressive behavior. A population-based sample of 317 preschool children was divided into four groups with different levels of aggression (moderate, borderline, clinical). Parents filled out questionnaires to assess service use (lifetime and past 3 months) and impact on family functioning. Over the past 3 months as well as over the first 4 years of life, children with a clinical level of aggression were more costly than children with a low level of aggression (mean total costs over the past 3 months: low € = 167,05 versus clinical € = 1034,83 and mean lifetime costs: low € = 817,37 versus clinical € = 1433,04), due to higher costs of services used by the child. In addition, families of children with a borderline or clinical level of aggressive behavior reported more impairment in their daily functioning than families of children with lower levels of aggression. The findings demonstrate that a high level of aggressive behavior results in high costs and impaired family functioning in the preschool years already.

Costs and consequences of clopidogrel versus aspirin for secondary prevention of ischaemic events in (high-risk) atherosclerotic patients in Sweden: a lifetime model based on the CAPRIE trial and high-risk CAPRIE subpopulations.

BACKGROUND: Antiplatelet therapy plays a central role in the prevention of atherothrombotic events. Both acetylsalicylic acid (aspirin) and clopidogrel have been shown to reduce the risk of recurrent cardiovascular events in various subgroups of patients with vascular disease. OBJECTIVE: To estimate the cost effectiveness of clopidogrel versus aspirin in Sweden for the prevention of atherothrombotic events based on CAPRIE trial data. The focus of this study is on two high-risk subpopulations: (i) patients with pre-existing symptomatic atherosclerotic disease; and (ii) patients with polyvascular disease. METHODS: A Markov model combining clinical, epidemiological and cost data was used to assess the economic value of clopidogrel compared with aspirin during a patient's lifetime. A societal perspective was used, with costs stated in Swedish kronor (SEK), year 2007 values. For the first 2 years, the clinical input for the model was based on the relevant subpopulations in the CAPRIE trial. Thereafter, transition probabilities were extrapolated, taking account of increased risks related to age and to a history of events. Cost effectiveness of 2 years of therapy is presented as cost per life-year gained (LYG) and as cost per QALY. Univariate and multivariate sensitivity analyses were performed to investigate robustness of results. RESULTS: For patients resembling the total CAPRIE population, who were treated with clopidogrel, the expected cost per LYG was SEK217,806 and the cost per QALY was estimated at SEK169,154. For the high-risk CAPRIE subpopulations, costs per QALY were lowest for patients with pre-existing symptomatic atherosclerotic disease (SEK38,153). Using a 'willingness-to-pay' perspective indicated that treatment with clopidogrel instead of aspirin in high-risk patients is associated with a high probability for cost effectiveness; 81% using a threshold of SEK100,000 per QALY and 98% using a threshold of SEK500,000 per QALY. Overall, the results appeared to be robust over the sensitivity analyses performed. CONCLUSION: When considering the cost-effectiveness categorization as proposed by the Swedish National Board of Health and Welfare, clopidogrel appears to be associated with costs per QALY that range from intermediate in the total CAPRIE population to low in high-risk atherosclerotic patients.

Modelling approaches: the case of schizophrenia.

Schizophrenia is a chronic disease characterized by periods of relative stability interrupted by acute episodes (or relapses). The course of the disease may vary considerably between patients. Patient histories show considerable inter- and even intra-individual variability. We provide a critical assessment of the advantages and disadvantages of three modelling techniques that have been used in schizophrenia: decision trees, (cohort and micro-simulation) Markov models and discrete event simulation models. These modelling techniques are compared in terms of building time, data requirements, medico-scientific experience, simulation time, clinical representation, and their ability to deal with patient heterogeneity, the timing of events, prior events, patient interaction, interaction between co-variates and variability (first-order uncertainty). We note that, depending on the research question, the optimal modelling approach should be selected based on the expected differences between the comparators, the number of co-variates, the number of patient subgroups, the interactions between co-variates, and simulation time. Finally, it is argued that in case micro-simulation is required for the cost-effectiveness analysis of schizophrenia treatments, a discrete event simulation model is best suited to accurately capture all of the relevant interdependencies in this chronic, highly heterogeneous disease with limited long-term follow-up data.

Cost-effectiveness of edoxaban compared to warfarin for the treatment and secondary prevention of venous thromboembolism in the UK.

Background: Venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is the third most common acute cardiovascular disease and represents an important burden for patients and payers. Objective: The aim was to estimate the cost-effectiveness of edoxaban, a non-VKA oral anticoagulant vs. warfarin, the currently most prescribed treatment for VTE in the UK. Study design: A Markov model was built using data from the Hokusai-VTE randomised controlled trial to estimate the lifetime costs and quality-adjusted life years (QALYs) in patients with VTE treated with edoxaban or warfarin over a lifetime horizon, from the UK National Health Services perspective. The model included VTE recurrences, VTE-related complications (post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension), and several types of bleeds associated with anticoagulation treatment. Patients were treated during a period of 6 months after the first VTE event, followed by flexible treatment duration (from 6 months to lifetime) after recurrence, i.e., tertiary prevention. Results: Edoxaban was found dominant vs. warfarin with 0.033 additional QALY and £55 less costs. The reduction of patient management costs, specifically monitoring costs, outweighed the higher drug costs. Edoxaban was dominant in all subgroups (index DVT only, all PE cases (PE with or without DVT), PE without DVT and PE with DVT). Cost-savings ranged from £54 to £81 while additional QALYs ranged from 0.031 to 0.046. Edoxaban was found dominant in 88.6% of cases and cost-effective in additional 10.9% of cases considering a £20,000 threshold in the probabilistic sensitivity analysis. Conclusion: Edoxaban may improve patients' quality of life in a lifetime horizon without additional costs for the healthcare system due to lower bleeding risk and no monitoring cost compared to warfarin.

Long-term clopidogrel therapy in patients receiving percutaneous coronary intervention.

BACKGROUND: The PCI-CURE (Percutaneous Coronary Intervention-Clopidogrel in Unstable Angina to Prevent Recurrent Events) and CREDO (Clopidogrel for the Reduction of Events During Observation) studies have demonstrated that, in addition to aspirin, pre-treatment with clopidogrel followed by long-term (i.e. 9-12 months) therapy significantly reduces the risk of atherothrombotic events in patients undergoing percutaneous coronary intervention (PCI). OBJECTIVE: To examine the economic implications, from the Dutch healthcare perspective, of the use of clopidogrel in patients undergoing PCI (elective procedures or in patients with acute coronary syndrome), comparing pre-treatment followed by long-term therapy with only 4 weeks of treatment. METHODS: A lifetime Markov model was used to combine data from the PCI-CURE and CREDO trials with data from the literature concerning epidemiology, costs and quality of life. The model was run separately for each trial. Only direct healthcare costs (euro, year 2004 values) were considered. Costs and outcomes were discounted at 4% per anum. For each trial, the cost effectiveness is expressed as costs per life-year and QALY gained. Uncertainties are addressed by uni- and probabilistic multivariate sensitivity analysis. RESULTS: When starting with the data from the PCI-CURE trial, pre-treatment plus 9-month clopidogrel therapy was predicted to save 1119 euros and gain 0.03 life-years and 0.07 QALYs per patient compared with short-term treatment. When starting with the data from the CREDO trial, the combination of pre-treatment and prolonged clopidogrel therapy (1 year) was estimated to save 497 euros and gain 0.10 life-years and 0.14 QALYs per patient. Univariate and probabilistic multivariate sensitivity analyses suggested that the conclusions were generally robust, but that the expected gain in survival for the PCI-CURE population was very sensitive to the effects on mortality within the combined endpoint of myocardial infarction/stroke-free survival. CONCLUSIONS: In The Netherlands, pre-treatment plus long-term (9-12 months) therapy with clopidogrel is estimated to save costs and increase (quality-adjusted) survival in the prevention of ischaemic events among patients undergoing elective PCI (CREDO) and in patients with acute coronary syndrome (PCI-CURE) compared with short-term treatment with clopidogrel without pre-treatment.

The Importance of Economic Perspective and Quantitative Approaches in Oncology Value Frameworks of Drug Selection and Shared Decision Making.

The debate around value in oncology drug selection has been prominent in recent years, and several professional bodies have furthered this debate by advocating for so-called value frameworks. Herein, we provide a viewpoint on these value frameworks, emphasizing the need to consider 4 key aspects: (1) the economic underpinnings of value; (2) the importance of the perspective adopted in the valuation; (3) the importance of the difference between absolute and relative measures of risk and measuring patient preferences; and (4) the recognition of multiple quality-of-life (QoL) domains, and the aggregation and valuation of those domains, through utilities within a multicriteria decision analysis, may allow prioritization of QoL above the tallying of safety events, particularly in a value framework focusing on the individual patient. While several frameworks exist, they incorporate different attributes and-importantly-assess value from alternative perspectives, including those of patients, regulators, payers, and society. The various perspectives necessarily lead to potentially different, if not sometimes divergent, conclusions about the valuation. We show that the perspective of the valuation affects the framing of the risk/benefit question and the methodology to measure the individual patient choice, or preference, as opposed to the collective, or population, choice. We focus specifically on the American Society of Clinical Oncology (ASCO) Value Framework. We argue that its laudable intent to assist in shared clinician-patient decision making can be augmented by more formally adopting methodology underpinned by micro- and health economic concepts, as well as application of formal quantitative approaches. Our recommendations for value frameworks focusing on the individual patient, such as the ASCO Value Framework, are 3-fold: (1) ensure that stakeholders understand the importance of the adopted (economic) perspective; (2) consider using exclusively absolute measures of risk and formal patient-preference methodology; and (3) consider foregoing safety parameters for higher-order utility considerations. DISCLOSURES: No funding was received for conceptualizing, writing, and/or editing this manuscript. Waldeck and White are employees of, and received stock option grants from, Celldex Therapeutics. Van Hout and Botteman are employees and shareholders of Pharmerit International. Pharmerit International is a research contractor for Celldex. All authors have retained editorial control of the content of the manuscript. Conceptualization of this viewpoint article was contributed primarily by Waldeck, along with Botteman, White, and van Hout. Data analysis and revision of the manuscript was contributed equally by all the authors. The manuscript was written by Waldeck, Botteman, van Hout, and White.

Clinical effectiveness of influenza vaccination in persons younger than 65 years with high-risk medical conditions: the PRISMA study.

BACKGROUND: Influenza vaccination has consistently been shown to prevent all-cause death and hospitalizations during influenza epidemics among seniors. However, such benefits have not yet been demonstrated among younger individuals with high-risk medical conditions. In the present study, we evaluated the effectiveness of influenza vaccine in persons recommended for vaccination of any age during an epidemic. METHODS: We conducted a case-control study during the 1999-2000 influenza A epidemic nested in a cohort of 75,227 primary care patients. End points were all-cause mortality and episodes of hospitalizations or general practitioner (GP) visits for influenza, pneumonia, other acute respiratory disease, acute otitis media, myocardial infarction, heart failure, and stroke. The effectiveness of vaccination was evaluated by means of logistic regression analysis with adjustments for age, sex, prior health care use, medication use, and comorbid conditions. RESULTS: Among high-risk children and adolescents younger than 18 years (n=5933; 8% of the study population), 1 death, 3 hospitalizations for pneumonia, and 160 GP visits occurred. After adjustments, 43% (95% confidence interval [CI], 10%-64%) of visits were prevented. Among high-risk adults aged between 18 and 64 years (n=24 928; 33% of the study population), 47 deaths, 23 hospitalizations, and 363 GP visits occurred. After adjustments, vaccination prevented 78% of deaths (95% CI, 39%-92%), 87% of hospitalizations (95% CI, 39%-97%), and 26% of GP visits (95% CI, 7%-47%). Among elderly persons (n=44 366; 59% of the study population), 272 deaths and 166 hospitalizations occurred, and after adjustments the vaccine prevented these end points by 50% (95% CI, 23%-68%) and 48% (95% CI, 7%-71%), respectively. CONCLUSION: Persons with high-risk medical conditions of any age can substantially benefit from annual influenza vaccination during an epidemic.

Three-year outcome after coronary stenting versus bypass surgery for the treatment of multivessel disease.

BACKGROUND: The primary results of Arterial Revascularization Therapy Study reported a greater need for repeated revascularization after percutaneous coronary intervention with stenting (PCI). However, PCI was less expensive than coronary artery bypass grafting (CABG) and offered the same degree of protection against death, stroke, and myocardial infarction. METHODS AND RESULTS: Patients with multivessel disease (n=1205) were randomly assigned to either CABG or PCI and followed up for up to 3 years. Survival rates without stroke or myocardial infarction were similar in each group at 1 year and 3 years (90.5% versus 91.4% for PCI versus CABG at 1 year and 87.2% versus 88.4% for PCI versus CABG at 3 years). However, the respective repeat revascularization rates were 21.2% and 26.7% at 1 and 3 years in patients allocated to PCI, compared with 3.8% and 6.6% in patients allocated to CABG (P<0.0001). Diabetes (P<0.0009) and maximal pressure for stent deployment (P<0.002) are the strongest independent predictors of events at 3 years after PCI, whereas left anterior descending coronary artery grafting (P<0.006) is the best predictor of event-free survival at 3 years after CABG. The incremental cost of surgery compared with PCI for an event-free patient was 19 257 at 1 year but decreased to 10 492 at 3 years. It remained at 142 391 at 3 years when revascularization procedures were excluded in the efficacy end point, however. CONCLUSIONS: Three-year survival rates without stroke and myocardial infarction are identical in both groups, and the cost/benefit ratio of stenting is determined primarily by the increasing need for revascularization in the PCI group.

Costs and effects of long-acting risperidone compared with oral atypical and conventional depot formulations in Germany.

Schizophrenia is one of the most expensive psychiatric conditions because of high direct and indirect costs associated with the nature of the illness, its resistance to treatment and the consequences of relapse. Long-acting risperidone is a new formulation of an atypical antipsychotic drug that also offers the improvements in compliance associated with haloperidol depot. The aim of this simulation study was to compare the benefits and costs of three pharmacological treatment strategies comprising first-line treatment with long-acting risperidone injection, a haloperidol depot or an oral atypical antipsychotic agent, over a 5-year period in Germany. A discrete event simulation model was developed to compare three treatment scenarios from the perspective of major third-party payers (sickness funds and social security 'Sozialversicherung'). The scenarios comprised first-line treatment with haloperidol depot (scenario 1), long-acting risperidone (scenario 2) and oral olanzapine (scenario 3). Switches to second or third-line options were allowed when side-effects occurred or a patient suffered more than a fixed number of relapses. The model accounted for fixed patient characteristics, and on the basis of these, simulated patient histories according to several time-dependent variables. The time horizon for this model was limited to 5 years, and in accordance with German guidelines, costs and effects were discounted by between 3 and 10%. Direct costs included medication, type of physician visits and treatment location. Indirect costs were not included. Information on treatment alternatives, transition probabilities, model structure and healthcare utilization were derived from the literature and an expert panel. Outcomes were expressed in terms of the number and duration of psychotic episodes, cumulative symptom scores, costs, and quality-adjusted life-years (QALY). Univariate sensitivity analyses were carried out, as were subgroup analyses based on disease severity and for patients at high risk of being non-compliant. The long-acting risperidone strategy was calculated to avoid 0.23 and 0.33 relapses per patient, decrease the cumulative symptom score by 25 and 33 points, and decrease the costs by 2017 Euro and 6096 Euro per patient (1608 Euro and 5422 Euro discounted), compared with the haloperidol depot and olanzapine strategies, respectively, over a 5-year period (year of costing 2004). Among high-risk non-compliant patients, long-acting risperidone was estimated to avoid 0.23 and 0.47 relapses and save 4822 Euro and 10,646 Euro per patient (4107 Euro and 9490 Euro discounted), compared with the haloperidol depot and olanzapine strategies, respectively. Sensitivity analyses showed that the results were robust and mainly sensitive to changes in the reported relative effectiveness of atypical and conventional formulations for preventing symptom recurrence, and in the relative compliance with oral and long-acting formulations. In this model, long-acting risperidone is a dominant strategy compared with a haloperidol depot or oral atypical antipsychotic agent, being both more effective and less costly over a 5-year period. Results for long-acting risperidone are even more favourable among patients at high risk of being noncompliant or with more severe disease.

Modelling the impact of compliance on the costs and effects of long-acting risperidone in Canada.

Schizophrenia is a chronic, relapsing disease that requires more healthcare resources to manage than any other single psychiatric illness. The main cost of treatment is hospitalization as a result of the exacerbation of symptoms often caused by poor compliance. Although the costs of hospitalization and relapse have been well documented, the differential effects of various medications on healthcare expenditure are still being determined. The aim of the present study was to estimate the cost effectiveness of long-acting risperidone in the treatment of high-risk, non-compliant patients with schizophrenia over a 5-year period in Canada. A discrete event model was developed comparing three scenarios, each with a different starting treatment: haloperidol depot, long-acting risperidone or oral risperidone. Second and third-line treatment options were olanzapine and clozapine, respectively, for all three scenarios. On the basis of 3000 simulated patient characteristics, the model generated individual patient histories. Outcomes included the number and duration of psychotic episodes, the cumulative Positive and Negative Syndrome Scale (PANSS) score and direct medical costs. The time horizon of the model was 5 years and a 5% discount rate was used for costs and effects. The perspective of the model was that of the Canadian healthcare system. After 5 years, treatment with long-acting risperidone saved Canada dollars 6908 and Canada dollars 13,130 (discounted) and avoided 0.28 and 0.54 relapses per patient, compared with haloperidol depot and oral risperidone, respectively. In this model, initiating treatment of high-risk, non-compliant patients with schizophrenia with long-acting risperidone was the dominant strategy. With long-acting risperidone, direct costs were lower and clinical effectiveness was greater, compared with haloperidol depot or oral risperidone, during years 4 and 5.

Modelling the treated course of schizophrenia: development of a discrete event simulation model.

In schizophrenia, modelling techniques may be needed to estimate the long-term costs and effects of new interventions. However, it seems that a simple direct link between symptoms and costs does not exist. Decisions about whether a patient will be hospitalized or admitted to a different healthcare setting are based not only on symptoms but also on social and environmental factors. This paper describes the development of a model to assess the dependencies between a broad range of parameters in the treatment of schizophrenia. In particular, the model attempts to incorporate social and environmental factors into the decision-making process for the prescription of new drugs to patients. The model was used to analyse the potential benefits of improving compliance with medication by 20% in patients in the UK. A discrete event simulation (DES) model was developed, to describe a cohort of schizophrenia patients with multiple psychotic episodes. The model takes into account the patient's sex, disease severity, potential risk of harm to self and society, and social and environmental factors. Other variables that change over time include the number of psychiatric consultations, the presence of psychotic episodes, symptoms, treatments, compliance, side-effects, the lack of ability to take care of him/herself, care setting and risk of harm. Outcomes are costs, psychotic episodes and symptoms. Univariate and multivariate sensitivity analyses were performed. Direct medical costs were considered (year of costing 2002), applying a 6.0% discount rate for costs and a 1.5% discount rate for outcome. The timeframe of the model is 5 years. When 50% of the decisions about the patient care setting are based on symptoms, a 20% increase in compliance was estimated to save 16,147 pounds and to avoid 0.55 psychotic episodes per patient over 5 years. Sensitivity analysis showed that the costs savings associated with increased compliance are robust over a range of variations in parameters. DES offers a flexible structure for modelling a disease, taking into account how a patient's history affects the course of the disease over time. This approach is particularly pertinent to schizophrenia, in which treatment decisions are complex. The model shows that better compliance increases the time between relapses, decreases the symptom score, and reduces the requirement for treatment in an intensive patient care setting, leading to cost savings. The extent of the cost savings depends on the relative importance of symptoms and of social and environmental factors in these decisions.

Modelling the cost-effectiveness of combination therapy for early, rapidly progressing rheumatoid arthritis by simulating the reversible and irreversible effects of the disease.

OBJECTIVE: To estimate the cost-effectiveness of adalimumab plus methotrexate (MTX) versus MTX monotherapy in early, aggressive rheumatoid arthritis (RA) when explicitly modelling short-term (reversible) and long-term (irreversible, ie, joint damage) disease activity and physical function. METHODS: A microsimulation model was developed to unify, in a single cost-effectiveness model, measures of reversible and irreversible disease activity and physical function based on data from the PREMIER trial. Short term, reversible disease activity was modelled using DAS28 variables, including swollen joint counts, tender joint counts, C reactive protein concentration and pain. The DAS28 variables were then used in a logistic regression to predict short-term American College of Rheumatology (ACR) responses, which informed treatment continuation and switches. Long term, irreversible, radiographically documented joint damage was modelled using modified Total Sharp Score (mTSS). The model then linked both short-term disease activity and mTSS to the Health Assessment Questionnaire score, which was used to calculate direct and indirect costs, and quality adjusted life-years (QALYs). RESULTS: When both reversible and irreversible effects of therapy were included, combination therapy was estimated to produce 6-month 50% ACR responses in 75% of patients versus 54% in MTX monotherapy. Compared to MTX monotherapy, combination therapy resulted in 2.68 and 3.04 discounted life years and QALYs gained, respectively. Combination therapy also resulted in a net increase in direct costs of £106,207 for a resulting incremental cost/QALY gain of £32,425. When indirect costs were included in the analysis, the ICER (incremental cost-effectiveness ratio) decreased to £27,238. Disregarding irreversible effects increased the incremental cost-effectiveness ratio to £78,809 (when only direct costs were included). CONCLUSIONS: Starting with adalimumab plus MTX combination therapy in early, aggressive RA is cost-effective when irreversible damage is adequately considered.

Cost-effectiveness Analysis of Rivaroxaban in the Secondary Prevention of Acute Coronary Syndromes in Sweden.

BACKGROUND: Worldwide, coronary heart disease accounts for 7 million deaths each year. In Sweden, acute coronary syndrome (ACS) is a leading cause of hospitalization and is responsible for 1 in 4 deaths. OBJECTIVE: The aim of this analysis was to assess the cost-effectiveness of rivaroxaban 2.5 mg twice daily (BID) in combination with standard antiplatelet therapy (ST-APT) versus ST-APT alone, for the secondary prevention of ACS in adult patients with elevated cardiac biomarkers without a prior history of stroke/transient ischemic attack (TIA), from a Swedish societal perspective, based on clinical data from the global ATLAS ACS 2-TIMI 51 trial, literature-based quality of life data and costs sourced from Swedish national databases. METHODS: A Markov model was developed to capture rates of single and multiple myocardial infarction (MI), ischemic and hemorrhagic stroke, thrombolysis in myocardial infarction (TIMI) major, minor, and "requiring medical attention" bleeds, revascularization events, and associated costs and utilities in patients who were stabilized after an initial ACS event. Efficacy and safety data for the first 2 years came from the ATLAS ACS 2-TIMI 51 trial. Long-term probabilities were extrapolated using safety and effectiveness of acetylsalicylic acid data, which was estimated from published literature, assuming constant rates in time. Future cost and effects were discounted at 3.0%. Univariate and probabilistic sensitivity analyses were conducted. RESULTS: In the base case, the use of rivaroxaban 2.5 mg BID was associated with improvements in survival and quality-adjusted life years (QALYs), yielding an incremental cost per QALY of 71,246 Swedish Krona (SEK) (€8045). The outcomes were robust to changes in inputs. The probabilistic sensitivity analysis demonstrated rivaroxaban 2.5 mg BID to be cost-effective in >99.9% of cases, assuming a willingness-to-pay threshold of SEK 500,000 (€56,458). CONCLUSION: Compared with ST-APT alone, the use of rivaroxaban 2.5 mg BID in combination with ST-APT can be considered a cost-effective treatment option for ACS patients with elevated cardiac biomarkers without a prior history of stroke/TIA in Sweden. FUNDING: Bayer Pharma AG.

A pharmacoeconomic comparison of the efficacy and costs of pantoprazole and omeprazole for the treatment of peptic ulcer or gastroesophageal reflux disease in The Netherlands.

BACKGROUND: The focus of treatment of patients with peptic ulcer or gastroesuphageal reflux disease has changed during the last 15 years, with a shift from histamine2-receptor antagonists to proton-pump inhibitors (PPIs). From 1993 to 2000, expenditures for omeprazole (90% of total market share of PPIs) increased in The Netherlands from 68 million euros to 230 million euros. In 1999, expenditures for pantoprazole accounted for the majority of the rest of the market share for PPIs. OBJECTIVE: The objective of this study was to compare the efficacy and costs of treatment with pantoprazole and omeprazole in The Netherlands. METHODS: First, we reviewed clinical studies that compared the efficacy of different dosages of omeprazole and pantoprazole. Second, we analyzed data from a nationwide database of drug prescriptions to determine the dosages used in daily practice in 1999. The data were based on a representative sample of approximately 40% of the Dutch community pharmacies. Third, we modeled the outcome of potential substitution of pantoprazole for omeprazole and the corresponding scenarios for nationwide cost savings using the prescription information from the nationwide database. Potential savings within the Dutch health care system were estimated. RESULTS: The 1999 prescription data indicated that pantoprazole treatment cost a mean 1.59 euros/d, compared with 2.12 euros/d for omeprazole (1.00 euro = 1.0487 US dollars). The mean cost per defined daily dose of omeprazole was 1.65 euros, compared with 1.59 euros for pantoprazole. Following the summary of product characteristics, treatment with pantoprazole appeared to be less costly for all indications. The projected annual cost savings for substituting pantoprazole for omeprazole on 90% of treatment days were estimated at 40.8 million euros. However, these projected savings may be offset by the costs of switching and the costs of upward dose adjustments that some patients may require. CONCLUSIONS: Based on the available documentation about effectiveness and costs of omeprazole and pantoprazole, pantoprazole may provide a more favorable pharmacoeconomic profile than omeprazole. However, this is only true if the substitution of omeprazole by pantoprazole can be achieved without loss of efficacy or tolerability.

Costs and effectiveness of using coumarins before, during and after coronary angioplasty.

BACKGROUND: In the Balloon Angioplasty and Anticoagulation Study (BAAS), coumarins added to routine aspirin therapy before coronary angioplasty reduced cardiac events at the cost of a slightly higher risk of bleeding complications. OBJECTIVE: To determine the cost effectiveness of coumarin treatment, based on the occurrence of both cardiac and bleeding events. METHODS: Effectiveness was measured, applying two definitions, in terms of the number of events occurring at one year. In the first definition, the occurrence of death, myocardial infarction (MI), or stroke was assessed. The second definition also included revascularisations and major bleeding episodes as an event. Costs were limited to direct medical costs. Cost effectiveness was addressed by probability ellipses representing the point estimates and uncertainties surrounding both costs and effectiveness. RESULTS: At 1 year, death, MI or stroke occurred 1.1% less often when treating with aspirin plus coumarins rather than aspirin therapy alone. When revascularisations and major bleeding events were also included, the difference was 5.0%. Overall, the additional costs in relation to coumarin treatment were compensated by a reduction in repeat interventions. When including all costs, the savings associated with coumarin treatment were estimated at Euros 235 per patient after 1 year. The probability that coumarins are cost saving was estimated at 0.85. The probability that coumarins combine additional effectiveness with cost savings was estimated at 0.70 when survival free of MI or stroke as an effectiveness measure was considered, and at 0.83 when survival free of MI, stroke, revascularisation or major bleeding was considered. CONCLUSION: Coumarin therapy added to routine aspirin therapy before coronary angioplasty, and continued during follow-up, may not only be considered more effective but also cost saving relative to aspirin therapy alone.