Patient-level Simulation Model Research Articles

Cost-Effectiveness of Hypochlorous Acid Preserved Wound Cleanser versus Saline Irrigation in Conjunction with Ultrasonic Debridement for Complex Wounds

Objective: Low-frequency ultrasound debridement with irrigation is an effective method of wound bed preparation. A recent clinical study compared hypochlorous acid preserved wound cleanser (HAPWOC) to saline and found HAPWOC to be a more effective adjunct to low frequency ultrasound debridement. However, HAPWOC has an added cost. The primary objective of this study was to assess the cost-effectiveness of HAPWOC as an irrigation modality with low-frequency ultrasound debridement for the treatment of severely complex wounds that were destined to be closed primarily via a flap. The secondary objective of this study was to estimate the number needed to treat (NNT) to avoid a wound-related complication and its expected cost per NNT. Methods: A patient-level Monte-Carlo simulation model was used to conduct a cost-effectiveness analysis from the US health system perspective. All clinical data were obtained from a prospective clinical trial. Cost data were obtained from the publicly available data sources in 2021 US dollars. The effect measure was the avoidance of wound-related complications at 14-days post-debridement. The primary outcome was the incremental cost-effectiveness ratio (ICER), a measure of the additional cost per benefit. The secondary outcomes were the NNT and expected cost per NNT to avoid one complication (complementary to the ICER in assessing cost-effectiveness). Deterministic and probabilistic sensitivity analyses (PSA) were performed to gauge the robustness and reliability of the results. Results: The ICER for HAPWOC versus saline irrigation was US$90.85 per wound complication avoided. The expected incremental cost per patient in the study and effect was US$49.97 with 55% relative reduction in wound-related complications at day 14 post debridement procedure. The NNT and cost per NNT were 2 and US$99.94, respectively. Sensitivity analyses demonstrated that these results were robust to variation in model parameters. Conclusion: HAPWOC was a cost-effective strategy for the treatment of complex wounds during ultrasonic debridement. For every two patients treated with HAPWOC, one complication was avoided.

Development and validation of the CHIME simulation model to assess lifetime health outcomes of prediabetes and type 2 diabetes in Chinese populations: A modeling study.

Existing predictive outcomes models for type 2 diabetes developed and validated in historical European populations may not be applicable for East Asian populations due to differences in the epidemiology and complications. Despite the continuum of risk across the spectrum of risk factor values, existing models are typically limited to diabetes alone and ignore the progression from prediabetes to diabetes. The objective of this study is to develop and externally validate a patient-level simulation model for prediabetes and type 2 diabetes in the East Asian population for predicting lifetime health outcomes. We developed a health outcomes model from a population-based cohort of individuals with prediabetes or type 2 diabetes: Hong Kong Clinical Management System (CMS, 97,628 participants) from 2006 to 2017. The Chinese Hong Kong Integrated Modeling and Evaluation (CHIME) simulation model comprises of 13 risk equations to predict mortality, micro- and macrovascular complications, and development of diabetes. Risk equations were derived using parametric proportional hazard models. External validation of the CHIME model was assessed in the China Health and Retirement Longitudinal Study (CHARLS, 4,567 participants) from 2011 to 2018 for mortality, ischemic heart disease, cerebrovascular disease, renal failure, cataract, and development of diabetes; and against 80 observed endpoints from 9 published trials using 100,000 simulated individuals per trial. The CHIME model was compared to United Kingdom Prospective Diabetes Study Outcomes Model 2 (UKPDS-OM2) and Risk Equations for Complications Of type 2 Diabetes (RECODe) by assessing model discrimination (C-statistics), calibration slope/intercept, root mean square percentage error (RMSPE), and R2. CHIME risk equations had C-statistics for discrimination from 0.636 to 0.813 internally and 0.702 to 0.770 externally for diabetes participants. Calibration slopes between deciles of expected and observed risk in CMS ranged from 0.680 to 1.333 for mortality, myocardial infarction, ischemic heart disease, retinopathy, neuropathy, ulcer of the skin, cataract, renal failure, and heart failure; 0.591 for peripheral vascular disease; 1.599 for cerebrovascular disease; and 2.247 for amputation; and in CHARLS outcomes from 0.709 to 1.035. CHIME had better discrimination and calibration than UKPDS-OM2 in CMS (C-statistics 0.548 to 0.772, slopes 0.130 to 3.846) and CHARLS (C-statistics 0.514 to 0.750, slopes -0.589 to 11.411); and small improvements in discrimination and better calibration than RECODe in CMS (C-statistics 0.615 to 0.793, slopes 0.138 to 1.514). Predictive error was smaller for CHIME in CMS (RSMPE 3.53% versus 10.82% for UKPDS-OM2 and 11.16% for RECODe) and CHARLS (RSMPE 4.49% versus 14.80% for UKPDS-OM2). Calibration performance of CHIME was generally better for trials with Asian participants (RMSPE 0.48% to 3.66%) than for non-Asian trials (RMPSE 0.81% to 8.50%). Main limitations include the limited number of outcomes recorded in the CHARLS cohort, and the generalizability of simulated cohorts derived from trial participants. Our study shows that the CHIME model is a new validated tool for predicting progression of diabetes and its outcomes, particularly among Chinese and East Asian populations that has been lacking thus far. The CHIME model can be used by health service planners and policy makers to develop population-level strategies, for example, setting HbA1c and lipid targets, to optimize health outcomes.

Decision models in type 2 diabetes mellitus: A systematic review

AimsTo reduce the burden of type 2 diabetes (T2DM), the disease decision model plays a vital role in supporting decision-making. Currently, there is no comprehensive summary and assessment of the existing decision models for T2DM. The objective of this review is to provide an overview of the characteristics and capabilities of published decision models for T2DM. We also discuss which models are suitable for different study demands.Materials and methodsFour databases (PubMed, Web of Science, Embase, and the Cochrane Library) were electronically searched for papers published from inception to August 2020. Search terms were: “Diabetes-Mellitus, Type 2”, “cost-utility”, “quality-of-life”, and “decision model”. Reference lists of the included studies were manually searched. Two reviewers independently screened the titles and abstracts following the inclusion and exclusion criteria. If there was insufficient information to include or exclude a study, then a full-text version was sought. The extracted information included basic information, study details, population characteristics, basic modeling methodologies, model structure, and data inputs for the included applications, model outcomes, model validation, and uncertainty.ResultsFourteen unique decision models for T2DM were identified. Markov chains and risk equations were utilized by four and three models, respectively. Three models utilized both. Except for the Archimedes model, all other models (n = 13) implemented an annual cycle length. The time horizon of most models was flexible. Fourteen models had differences in the division of health states. Ten models emphasized macrovascular and microvascular complications. Six models included adverse events. Majority of the models (n = 11) were patient-level simulation models. Eleven models simulated annual changes in risk factors (body mass index, glycemia, HbA1c, blood pressure (systolic and/or diastolic), and lipids (total cholesterol and/or high-density lipoprotein)). All models reported the main data sources used to develop health states of complications. Most models (n = 11) could deal with the uncertainty of models, which were described in varying levels of detail in the primary studies. Eleven studies reported that one or more validation checks were performed.ConclusionsThe existing decision models for T2DM are heterogeneous in terms of the level of detail in the classification of health states. Thus, more attention should be focused on balancing the desired level of complexity against the required level of transparency in the development of T2DM decision models.

PND33 A Cost-Effectiveness Analysis of Fenfluramine for the Treatment of Seizures for Patients with Dravet Syndrome (DS) in the UK Setting

DS is a rare, genetic epileptic encephalopathy presenting in early childhood, characterised by frequent, severe and pharmaco-resistant seizures; associated with developmental and cognitive impairment, premature death and poor patient and carer quality of life (QoL). As DS is highly heterogeneous, a novel patient-level simulation model was developed to evaluate the cost-effectiveness of fenfluramine - a newly licensed ‘add-on therapy’ for the treatment of DS, in the UK setting. Patient-level data from the placebo arm of fenfluramine registration studies were used to model the number of convulsive seizures and convulsive seizure-free days per 28-day cycle in a DS population generalisable to the UK. Utility values were mapped from patient and carer QoL data from the trials. Carer utility values were included in line with the NICE reference case. Natural and DS-specific mortality rates were derived from literature and UK healthcare resource use data from a DS-specific pathway study. The primary base case analysis compared standard of care (SoC) with either add-on fenfluramine or NICE-recommended cannabidiol (with clobazam), over a lifetime horizon. A robust indirect treatment comparison provided relative treatment effects for SoC, fenfluramine and cannabidiol. The estimated ICER of fenfluramine at the proposed NHS price compared with cannabidiol (list price) is £31,773/QALY. Deterministic and probabilistic sensitivity analyses demonstrated the base case analysis results are robust to parameter uncertainty. Scenario analyses indicate the most influential assumptions are the inclusion of utility values for carers, and doses assumed for cannabidiol. At plausible maximum doses of cannabidiol, fenfluramine dominates cannabidiol. In fully incremental analyses, fenfluramine had a lower ICER vs SoC than did cannabidiol, i.e. fenfluramine extendedly dominated cannabidiol. This novel patient-level simulation model, which appropriately characterises the population heterogeneity in DS, demonstrates fenfluramine provides a clinically and cost-effective alternative to existing ‘add-on therapy’ options for this rare, life-threatening syndrome.

PRS31 Modelling Survival of People with Cystic Fibrosis (PWCF) Aged ≥12 YEARS Homozygous for the F508DEL Mutation Treated with Ivacaftor/Tezacaftor/Elexacaftor and Ivacaftor (IVA/TEZ/ELX)

IVA/TEZ/ELX is a novel cystic fibrosis transmembrane conductance modulator (CFTRm) therapy approved by the European Medicines Agency to treat the underlying cause of disease for pwCF aged ≥12 years homozygous for the F508del mutation (F/F) or heterozygous for F508del and a minimal function mutation. A simulation model was used to estimate survival benefit of IVA/TEZ/ELX in F/F pwCF. A validated, lifetime, patient-level simulation model was used to estimate median survival in a simulated cohort of F/F pwCF aged ≥12 years in the United Kingdom (UK) treated with: IVA/TEZ/ELX+best supportive care (BSC), tezacaftor/ivacaftor (TEZ/IVA)+BSC, and BSC-alone. Age-specific mortality hazards from the 2008 UK CF Registry were combined with a Cox proportional hazards model to predict survival based on several risk factors in pwCF. Clinical efficacy inputs for IVA/TEZ/ELX+BSC and TEZ/IVA+BSC were derived from an indirect treatment comparison conducted using data from the IVA/TEZ/ELX Phase 3b study (NCT04105972) and TEZ/IVA Phase 3 study (NCT02347657). CFTRm impact on long-term lung function decline was based on TEZ/IVA data. Median projected survival in BSC-treated pwCF was 37.8 years; median projected survival increased to 47.9 years in TEZ/IVA-treated pwCF and 59.1 years in IVA/TEZ/ELX+BSC-treated pwCF, leading to an incremental survival increase with IVA/TEZ/ELX+BSC of 11.2 years versus TEZ/IVA+BSC and 21.3 years versus BSC-alone. Patients initiating IVA/TEZ/ELX+BSC treatment at age 12 years were projected to live 15.6 years more than TEZ/IVA+BSC-treated (74.4 vs 58.8 years) and 37.5 years more than BSC-alone–treated (74.4 vs 36.9 years) pwCF. At 10 years, 83% of IVA/TEZ/ELX+BSC-treated pwCF were alive versus 73% and 57% of TEZ/IVA+BSC-treated and BSC-alone–treated pwCF, respectively. Based on these simulations, treatment with IVA/TEZ/ELX+BSC is projected to substantially increase survival for pwCF aged ≥12 years with the F/F genotype in the UK. Treatment initiation at the youngest indicated age is projected to provide even greater survival benefit.

PRS2 Modelling Survival of People with Cystic Fibrosis (PWCF) Aged ≥12 YEARS Heterozygous for the F508DEL Mutation with a Minimal Function Mutation Treated with Ivacaftor/Tezacaftor/Elexacaftor and Ivacaftor (IVA/TEZ/ELX)

IVA/TEZ/ELX is a novel cystic fibrosis transmembrane conductance modulator (CFTRm) therapy approved by the European Medicines Agency to treat the underlying cause of disease for pwCF aged ≥12 years homozygous for the F508del mutation or heterozygous for F508del and a minimal function mutation (F/MF). In the absence of long-term real-world data, a simulation model was used to estimate survival in the F/MF population receiving IVA/TEZ/ELX plus best supportive care (BSC) versus BSC-alone. A validated, lifetime, patient-level simulation model was used to estimate median survival of a simulated cohort of F/MF pwCF aged ≥12 years in the United Kingdom (UK) with and without IVA/TEZ/ELX treatment. Age-specific mortality hazards from the 2008 UK CF Registry were combined with a Cox proportional hazards model to predict survival based on several risk factors in pwCF. Clinical efficacy inputs were derived from the Phase 3 study in the F/MF population (NCT03525444). IVA/TEZ/ELX impact on long-term lung function decline was based on other CFTRm data. Outcomes were also evaluated for a simulated cohort initiating treatment at age 12 years and using a 10-year model horizon. Median projected survival in pwCF on BSC was 37.8 years; median projected survival increased to 59.9 years in IVA/TEZ/ELX+BSC-treated pwCF, leading to an increase in incremental survival with IVA/TEZ/ELX+BSC of 22.0 years versus BSC-alone. pwCF initiating IVA/TEZ/ELX+BSC treatment at age 12 years were projected to live 36.9 years more than pwCF receiving BSC-alone (73.8 vs 36.9 years). At 10 years, 83% of pwCF receiving IVA/TEZ/ELX+BSC were projected to be alive versus 56% of patients receiving BSC-alone. Based on these simulations, treatment with IVA/TEZ/ELX+BSC is projected to increase median survival by more than 2 decades for F/MF pwCF aged ≥12 years in the UK. Treatment initiation at the youngest indicated age (i.e., age 12 years) leads to even greater projected survival benefits.

Modeling Early Warning Systems: Construction and Validation of a Discrete Event Simulation Model for Heart Failure

ObjectivesDeveloping and validating a discrete event simulation model that is able to model patients with heart failure managed with usual care or an early warning system (with or without a diagnostic algorithm) and to account for the impact of individual patient characteristics in their health outcomes. MethodsThe model was developed using patient-level data from the Trans-European Network – Home-Care Management System study. It was coded using RStudio Version 1.3.1093 (version 3.6.2.) and validated along the lines of the Assessment of the Validation Status of Health-Economic decision models tool. The model includes 20 patient and disease characteristics and generates 8 different outcomes. Model outcomes were generated for the base-case analysis and used in the model validation. ResultsPatients managed with the early warning system, compared with usual care, experienced an average increase of 2.99 outpatient visits and a decrease of 0.02 hospitalizations per year, with a gain of 0.81 life years (0.45 quality-adjusted life years) and increased average total costs of €11 249. Adding a diagnostic algorithm to the early warning system resulted in a 0.92 life year gain (0.57 quality-adjusted life years) and increased average costs of €9680. These patients experienced a decrease of 0.02 outpatient visits and 0.65 hospitalizations per year, while they avoided being hospitalized 0.93 times. The model showed robustness and validity of generated outcomes when comparing them with other models addressing the same problem and with external data. ConclusionsThis study developed and validated a unique patient-level simulation model that can be used for simulating a wide range of outcomes for different patient subgroups and treatment scenarios. It provides useful information for guiding research and for developing new treatment options by showing the hypothetical impact of these interventions on a large number of important heart failure outcomes.

Comparative Cost and Effectiveness of a New Algorithm for Early Lyme Disease Diagnosis: Evaluation in US, Germany, and Italy.

PurposeThis Lyme disease early detection economic model, for patients with suspected Lyme disease without erythema migrans (EM), compares outcomes of standard two-tier testing (sTTT), modified two-tier testing (mTTT) and the DiaSorin Lyme Detection Algorithm (LDA), a combination of both serology tests and Interferon-ɤ Release Assay.Patients and MethodsA patient-level simulation model was built to incorporate effectiveness estimation from a structured focused literature review, and health-care cost inputs for the United States, Germany, and Italy. Simulated clinical outcomes were 1) percent of patients with timely and correct diagnosis, 2) patients appropriately treated and exposed to antibiotics therapy, and 3) patients with late Lyme disease manifestations. Expected health outcomes were expressed in terms of differences in quality-adjusted life years (QALYs) due to disseminated Lyme disease and persisting symptoms, and economic outcomes were analyzed from a third-party payer perspective.ResultsThe DiaSorin LDA resulted in a better sensitivity compared to sTTT and mTTT, 84% vs 49% and 45%, respectively, in the base case (13% of infected patients in the tested population). Due to the improved diagnostic performance, the LDA-based strategy is expected to be more effective, providing mean incremental 0.024 QALYs per tested patient, or 0.19 per infected patient. Furthermore, from a third-party payer perspective, the adoption of the LDA-based strategy would reduce the expected health-care cost for suspected and confirmed Lyme disease by roughly 40%, ie about $410, €130, and €170 per tested patient in the United States, Germany, and Italy, respectively, compared to sTTT. The results are most sensitive to the infection rate in the tested population, with LDA maintaining a cost advantage for Lyme disease active infection rates ≥0.8-2.5%.ConclusionLDA early diagnostic testing and subsequent treatment of subjects with early Lyme disease without EM are expected to outperform traditional management strategies both clinically and economically in the US, Germany, and Italy.

Cost-effectiveness of Novel Treatment Sequences for Transplant-Ineligible Patients With Multiple Myeloma

Although the number of treatments for elderly patients with non-transplant-eligible (NTE) multiple myeloma (MM) has increased substantially, evidence is lacking on the clinical effectiveness and cost-effectiveness of novel treatment sequences. To determine the optimal sequence of treatment for patients with NTE MM from the perspective of the patient, physician, and society. Using data from a Dutch observational registry, this economic evaluation combined evidence from network meta-analyses in a patient-level simulation model and modeled time-to-event and types of events from a hospital perspective with a lifetime horizon. Data analysis was performed from June 2019 to September 2020. Thirty treatment sequences, including up to 3 lines of therapy, were compared with bortezomib-melphalan-prednisone (VMP)-lenalidomide-dexamethasone (LenDex)-pomalidomide-dexamethasone (PomDex). The primary outcomes of the model were overall survival (OS), quality-adjusted life-years (QALYs), costs, and cost-effectiveness. Sequences starting with daratumumab-VMP (second line: carfilzomib-lenalidomide-dexamethasone or elotuzumab-lenalidomide-dexamethasone) or bortezomib-melphalan-prednisone-thalidomide-maintenance bortezomib-thalidomide (VMPT-VT) (second line: daratumumab-lenalidomide-dexamethasone) had the largest expected OS (7.5 years), which is 3.5 additional life-years compared with VMP-LenDex-PomDex. Total costs per patient for these sequences ranged between $786 024 and $1 085 794. The sequence VMPT-VT-carfilzomib-lenalidomide-dexamethasone-panobinostat-bortezomib-dexamethasone had the most favorable cost-effectiveness ratio ($98 585 per life-year gained and $132 707 per QALY gained vs VMP-LenDex-PomDex). These findings suggest that sequences including novel treatments were highly effective, but the cost-effectiveness ratios were above currently accepted willingness-to-pay thresholds. Treating MM with novel agents necessitates either a large increase in budget or a substantial reduction of drug costs by price negotiations, and these findings can support these reimbursement decisions and price negotiations.

Cost-Effectiveness of Dual Bronchodilator Indacaterol/Glycopyrronium for COPD Treatment in China.

BackgroundIndacaterol/glycopyrronium (IND/GLY) is a once-daily dual bronchodilator for long-term treatment of patients with chronic obstructive pulmonary disease (COPD). The efficacy and safety of IND/GLY have been proved before, but the cost-effectiveness is unknown in China.PurposeThis study assessed cost-effectiveness of IND/GLY comparing with salmeterol/fluticasone (SAL/FLU) and tiotropium.MethodsA patient-level simulation model was established from Chinese payer perspective. Patient parameters were randomly simulated through resampling from parameter distributions based on clinical trials and China-specific cost data to represent individual level health state and health state transitions in the model. We simulated patient-level health state, costs, life years (LYs) and quality-adjusted life years (QALYs) of whole life horizon to evaluate the cost-effectiveness of IND/GLY comparing with SAL/FLU and tiotropium respectively.ResultsComparing with SAL/FLU, IND/GLY resulted in 0.384 LYs and 0.255 QALYs gained. The incremental cost-effectiveness ratio (ICER) is −35,822 CNY/LY and the incremental cost-utility ratio (ICUR) is −53,834 CNY/QALY for IND/GLY versus SAL/FLU. Comparing with tiotropium, IND/GLY resulted in 0.232 LYs and 0.146 QALYs gained. The ICER is 39,729 CNY/LY and the ICUR is 63,246 CNY/QALY for IND/GLY versus tiotropium.ConclusionThis study found that dual bronchodilator IND/GLY is cost-effective for stable COPD treatment in China from Chinese payer's perspective.

1604. Cost-Effectiveness of Ceftazidime-Avibactam for Patients with Hospital-Acquired Pneumonia Caused by Multi-Drug Resistant Enterobacteriaceae or Pseudomonas in China

BackgroundTo estimate the cost-effectiveness of ceftazidime-avibactam (CAZ-AVI) for the treatment of hospital-acquired pneumonia (HAP) including ventilator-associated pneumonia (VAP) caused by multi-drug resistant enterobacteriaceae (MDRE) or MDR pseudomonas aeruginosa (MDRPA) in China.MethodsA previously published patient-level simulation model was localized to China to estimate the cost-effectiveness of first-line CAZ-AVI compared to meropenem from a healthcare perspective. Patients flowed through the model which evaluates resistance status, response, and adverse events (AEs), which can all lead to a treatment switch. Second-line therapy of colistin plus high dose meropenem was used for both arms. Resistance rates were 0.7% (CAZ-AVI) and 7.6% (meropenem) for MDRE, and 10.7% (CAZ-AVI) and 35.5% (meropenem) for MDRPA. Effectiveness rates for CAZ-AVI and meropenem were based on a randomized, double-blind, phase 3 clinical trial. All cost data, including drugs, AEs, and hospitalization were localized to China. Utility values were based on response and sourced from the literature. Costs and benefits were discounted at 5% over the five year time horizon.ResultsAt a cost-effectiveness threshold of three-times GDP per capita, CAZ-AVI was cost-effective compared to meropenem for HAP/VAP caused by both MDRE and MDRPA with ICERs of ¥147,500 and ¥30,496, respectively. Specifically, CAZ-AVI had ¥13,699 and 0.09 additional total costs and QALYs, respectively, within MDRE; ¥5,207 and 0.17 additional total costs and QALYs, respectively, within MDRPA. Length of stay was reduced by 0.65 days and 1.37 in the CAZ-AVI arms of the MDRE and MDRPA analyses, respectively.ConclusionCAZ-AVI is a cost-effective alternative to meropenem in the treatment of HAP/VAP caused by MDRE or MDRPA in China.DisclosuresWesley Furnback, BA, Pfizer (Consultant) YiXi Chen, MSc, Pfizer (Employee) Peng Dong, PhD, Pfizer (Employee) Bruce Wang, PhD, Pfizer (Consultant) Wajeeha Ansari, MSc, Pfizer (Employee) Claudie Charbonneau, PhD, Pfizer (Employee) Hengjing Dong, MD, Pfizer (Other Financial or Material Support, Honorarium)

Empagliflozin in Type 2 Diabetes Mellitus Patients with High Cardiovascular Risk: A Model-Based Cost-Utility Analysis in China.

PurposeTo evaluate the cost-utility of empagliflozin, in addition to best available standard care (BASC), for the treatment of adult patients with T2DM at high cardiovascular risk from the Chinese healthcare system perspective.MethodsA Microsoft Excel-based patient-level simulation model, based on the EMPA-REG OUTCOME trial data, was adapted and used to project individual’s clinical and economic outcomes over a lifetime horizon. The cost and utility values were derived from databases and published studies. Numbers and rates of diabetes-related events, life-years (LYs), quality-adjusted life-years (QALYs), costs (¥ 2019) as well as incremental cost-utility ratios (ICURs) were calculated. Deterministic and probabilistic sensitivity analyses were conducted to test the robustness of the model results.ResultsCompared with BASC, empagliflozin plus BASC was predicted to result in an additional 1.01 QALYs (8.05 QALYs vs 7.04 QALYs) at an incremental cost of ¥4002 per patient. The modeled ICUR was ¥3988 per QALY gained, which was considered highly cost-effective in China compared to both one and three times the GDP per capita in 2019 (¥70,892 and ¥212,676). The deterministic and probabilistic sensitivity analyses confirmed the robustness of base-case results.ConclusionThis is the first cost-utility analysis regarding the use of empagliflozin in patients with T2DM in China, the world’s most affected country by the T2DM pandemic. The economic evaluation suggests that empagliflozin added to BASC was estimated to be a highly value-for-money option for the treatment of adult patients with T2DM at high cardiovascular risk in the Chinese healthcare setting.

How to Address Uncertainty in Health Economic Discrete-Event Simulation Models: An Illustration for Chronic Obstructive Pulmonary Disease.

Background. Evaluation of personalized treatment options requires health economic models that include multiple patient characteristics. Patient-level discrete-event simulation (DES) models are deemed appropriate because of their ability to simulate a variety of characteristics and treatment pathways. However, DES models are scarce in the literature, and details about their methods are often missing. Methods. We describe 4 challenges associated with modeling heterogeneity and structural, stochastic, and parameter uncertainty that can be encountered during the development of DES models. We explain why these are important and how to correctly implement them. To illustrate the impact of the modeling choices discussed, we use (results of) a model for chronic obstructive pulmonary disease (COPD) as a case study. Results. The results from the case study showed that, under a correct implementation of the uncertainty in the model, a hypothetical intervention can be deemed as cost-effective. The consequences of incorrect modeling uncertainty included an increase in the incremental cost-effectiveness ratio ranging from 50% to almost a factor of 14, an extended life expectancy of approximately 1.4 years, and an enormously increased uncertainty around the model outcomes. Thus, modeling uncertainty incorrectly can have substantial implications for decision making. Conclusions. This article provides guidance on the implementation of uncertainty in DES models and improves the transparency of reporting uncertainty methods. The COPD case study illustrates the issues described in the article and helps understanding them better. The model R code shows how the uncertainty was implemented. For readers not familiar with R, the model’s pseudo-code can be used to understand how the model works. By doing this, we can help other developers, who are likely to face similar challenges to those described here.

A Patient-Level Model to Estimate Lifetime Health Outcomes of Patients With Type 1 Diabetes.

OBJECTIVETo develop a patient-level simulation model for predicting lifetime health outcomes of patients with type 1 diabetes and as a tool for economic evaluation of type 1 diabetes treatment based on data from a large, longitudinal cohort.RESEARCH DESIGN AND METHODSData for model development were obtained from the Swedish National Diabetes Register. We derived parametric proportional hazards models predicting the absolute risk of diabetes complications and death based on a wide range of clinical variables and history of complications. We used linear regression models to predict risk factor progression. Internal validation was performed, estimates of life expectancies for different age-sex strata were computed, and the impact of key risk factors on life expectancy was assessed.RESULTSThe study population consisted of 27,841 patients with type 1 diabetes with a mean duration of follow-up of 7 years. Internal validation showed good agreement between the predicted and observed cumulative incidence of death and 10 complications. Simulated life expectancy was ∼13 years lower than that of the sex- and age-matched general population, and patients with type 1 diabetes could expect to live with one or more complications for ∼40% of their remaining life. Sensitivity analysis showed the importance of preventing renal dysfunction, hypoglycemia, and hyperglycemia as well as lowering HbA1c in reducing the risk of complications and death.CONCLUSIONSOur model was able to simulate risk factor progression and event histories that closely match the observed outcomes and to project events occurring over patients’ lifetimes. The model can serve as a tool to estimate the impact of changing clinical risk factors on health outcomes to inform economic evaluations of interventions in type 1 diabetes.

Accurately Reflecting Uncertainty When Using Patient-Level Simulation Models to Extrapolate Clinical Trial Data

Introduction. Patient-level simulation models facilitate extrapolation of clinical trial data while allowing for heterogeneity, prior history, and nonlinearity. However, combining different types of uncertainty around within-trial and extrapolated results remains challenging. Methods. We tested 4 methods to combine parameter uncertainty (around the regression coefficients used to predict future events) with sampling uncertainty (uncertainty around mean risk factors within the finite sample whose outcomes are being predicted and the effect of treatment on these risk factors). We compared these 4 methods using a simulation study based on an economic evaluation extrapolating the AFORRD randomized controlled trial using the UK Prospective Diabetes Study Outcomes Model version 2. This established type 2 diabetes model predicts patient-level health outcomes and costs. Results. The 95% confidence intervals around life years gained gave 25% coverage when sampling uncertainty was excluded (i.e., 25% of 95% confidence intervals contained the “true” value). Allowing for sampling uncertainty as well as parameter uncertainty widened confidence intervals by 6.3-fold and gave 96.3% coverage. Methods adjusting for baseline risk factors that combine sampling and parameter uncertainty overcame the bias that can result from between-group baseline imbalance and gave confidence intervals around 50% wider than those just considering parameter uncertainty, with 99.8% coverage. Conclusions. Analyses extrapolating data for individual trial participants should include both sampling uncertainty and parameter uncertainty and should adjust for any imbalance in baseline covariates.

A patient-level cost-effectiveness analysis of iron isomaltoside versus ferric carboxymaltose for the treatment of iron deficiency anemia in the United Kingdom

Objectives: Intravenous iron is the recommended treatment for patients with iron deficiency anemia (IDA) where oral iron is ineffective or rapid iron replenishment is required. Two high-dose, rapid-administration intravenous iron formulations are currently available in the UK: iron isomaltoside 1000/ferric derisomaltose (IIM) and ferric carboxymaltose (FCM). An indirect treatment comparison (ITC) recently showed that improvement from baseline hemoglobin was significantly larger with IIM than FCM. The objective was to use the ITC findings to evaluate the cost-effectiveness of IIM versus FCM from the UK healthcare payer perspective.Methods: A patient-level simulation model was developed in R to evaluate the cost per patient experiencing hematological response with IIM versus FCM. The model generated a simulated cohort from parametric distributions of baseline hemoglobin and bodyweight. Changes in hemoglobin were modeled based on data from the ITC, covaried with baseline hemoglobin based on patient-level data from a randomized controlled trial. Posological models of the iron formulations were developed based on the summaries of product characteristics. UK-specific costs were based on healthcare resource groups.Results: The proportion of patients experiencing hematological response was 9.0% higher with IIM relative to FCM (79.0% versus 70.0%), based on modeling of clinically realistic, correlated distributions of baseline hemoglobin and change from baseline hemoglobin. The mean number of infusions needed to administer the required dose was 1.92 with FCM, versus 1.38 with IIM, resulting in costs of £637 and £457 per treated patient with FCM and IIM respectively, corresponding to respective costs of £910 and £579 per responder.Conclusions: The analysis showed that using IIM rather than FCM in patients with IDA was dominant and would reduce the number of iron infusions required to correct iron deficiency, thereby reducing the costs associated with IDA treatment and simultaneously increasing the proportion of patients with IDA experiencing a clinically meaningful hematological response.

Addressing Challenges of Economic Evaluation in Precision Medicine Using Dynamic Simulation Modeling

ObjectivesThe objective of this article is to describe the unique challenges and present potential solutions and approaches for economic evaluations of precision medicine (PM) interventions using simulation modeling methods. MethodsGiven the large and growing number of PM interventions and applications, methods are needed for economic evaluation of PM that can handle the complexity of cascading decisions and patient-specific heterogeneity reflected in the myriad testing and treatment pathways. Traditional approaches (eg, Markov models) have limitations, and other modeling techniques may be required to overcome these challenges. Dynamic simulation models, such as discrete event simulation and agent-based models, are used to design and develop mathematical representations of complex systems and intervention scenarios to evaluate the consequence of interventions over time from a systems perspective. ResultsSome of the methodological challenges of modeling PM can be addressed using dynamic simulation models. For example, issues regarding companion diagnostics, combining and sequencing of tests, and diagnostic performance of tests can be addressed by capturing patient-specific pathways in the context of care delivery. Issues regarding patient heterogeneity can be addressed by using patient-level simulation models. ConclusionThe economic evaluation of PM interventions poses unique methodological challenges that might require new solutions. Simulation models are well suited for economic evaluation in PM because they enable patient-level analyses and can capture the dynamics of interventions in complex systems specific to the context of healthcare service delivery.

Early cost-utility analysis of tissue-engineered heart valves compared to bioprostheses in the aortic position in elderly patients

ObjectivesAortic valve disease is the most frequent indication for heart valve replacement with the highest prevalence in elderly. Tissue-engineered heart valves (TEHV) are foreseen to have important advantages over currently used bioprosthetic heart valve substitutes, most importantly reducing valve degeneration with subsequent reduction of re-intervention. We performed early Health Technology Assessment of hypothetical TEHV in elderly patients (≥ 70 years) requiring surgical (SAVR) or transcatheter aortic valve implantation (TAVI) to assess the potential of TEHV and to inform future development decisions.MethodsUsing a patient-level simulation model, the potential cost-effectiveness of TEHV compared with bioprostheses was predicted from a societal perspective. Anticipated, but currently hypothetical improvements in performance of TEHV, divided in durability, thrombogenicity, and infection resistance, were explored in scenario analyses to estimate quality-adjusted life-year (QALY) gain, cost reduction, headroom, and budget impact.ResultsDurability of TEHV had the highest impact on QALY gain and costs, followed by infection resistance. Improved TEHV performance (− 50% prosthetic valve-related events) resulted in lifetime QALY gains of 0.131 and 0.043, lifetime cost reductions of €639 and €368, translating to headrooms of €3255 and €2498 per hypothetical TEHV compared to SAVR and TAVI, respectively. National savings in the first decade after implementation varied between €2.8 and €11.2 million (SAVR) and €3.2–€12.8 million (TAVI) for TEHV substitution rates of 25–100%.ConclusionsDespite the relatively short life expectancy of elderly patients undergoing SAVR/TAVI, hypothetical TEHV are predicted to be cost-effective compared to bioprostheses, commercially viable and result in national cost savings when biomedical engineers succeed in realising improved durability and/or infection resistance of TEHV.

Cost-effectiveness analysis comparing ceftazidime/avibactam (CAZ-AVI) as empirical treatment comparing to ceftolozane/tazobactam and to meropenem for complicated intra-abdominal infection (cIAI)

BackgroundThe rising incidence of resistance to currently available antibiotics among pathogens, particularly Gram-negative pathogens, in complicated intra-abdominal infections (cIAIs) has become a challenge for clinicians. Ceftazidime/avibactam (CAZ-AVI) is a fixed-dose antibiotic approved in Europe and the United States for treating (in combination with metronidazole) cIAI in adult hospitalised patients who have limited or no alternative treatment options. The approval was based on the results of RECLAIM, a Phase III, parallel-group, comparative study (RECLAIM 1 [NCT01499290] and RECLAIM 2 [NCT01500239]). The objective of our study was to assess the cost-effectiveness of CAZ-AVI plus metronidazole compared with 1) ceftolozane/tazobactam plus metronidazole and 2) meropenem, as an empiric treatment for the management of cIAI in Italy.MethodsA sequential, patient-level simulation model, with a 5-year time horizon and 3% annual discount rate (applied to both costs and health benefits), was developed using Microsoft Excel® to demonstrate the clinical course of the disease. The impact of resistant pathogens was included as an additional factor.ResultsIn the base-case analysis, the CAZ-AVI sequence (CAZ-AVI plus metronidazole followed by a colistin + tigecycline + high-dose meropenem combination after treatment failure), when compared to sequences for ceftolozane/tazobactam (ceftolozane/tazobactam plus metronidazole followed by colistin + tigecycline + high-dose meropenem after treatment failure) and meropenem (meropenem followed by colistin + tigecycline + high-dose meropenem after treatment failure), had better clinical outcomes with higher cure rates (93.04% vs. 91.52%; 92.98% vs. 90.24%, respectively), shorter hospital stays (∆ = − 0.38 and ∆ = − 1.24 days per patient, respectively), and higher quality-adjusted life years (QALYs) gained per patient (4.021 vs. 3.982; 4.019 vs. 3.960, respectively). The incremental cost effectiveness ratio in the CAZ-AVI sequence was €4099 and €15,574 per QALY gained versus each comparator sequence, respectively, well below the willingness-to-pay threshold of €30,000 per QALY accepted in Italy.ConclusionsThe model results demonstrated that CAZ-AVI plus metronidazole could be a cost-effective alternative when compared with other antibiotic treatment options, as it is expected to provide better clinical benefits in hospitalised patients with cIAI in Italy.

PCV155 COST-EFFECTIVENESS OF SECOND-LINE CEFTAZIDIME-AVIBACTAM IN PATIENTS WITH HOSPITAL-ACQUIRED PNEUMONIA INCLUDING VENTILATOR-ASSOCIATED PNEUMONIA IN TAIWAN

This study evaluates the cost-effectiveness of ceftazidime-avibactam (CAZ-AVI), a novel combination antibiotic, as first-line therapy for patients with hospital-acquired pneumonia (HAP) including ventilator-associated pneumonia (VAP) in Taiwan. A previously developed patient-level simulation model evaluating the cost-effectiveness of CAZ-AVI in complicated urinary tract infections, complicated intra-abdominal infections, and HAP (incl. VAP), was localized to Taiwan. HAP (incl. VAP)-causing pathogens E. coli, K. pneumonia, E. Cloacae, and P. aeruginosa were included using prevalence rates from the 2015 Taiwan Nosocomial Infections Surveillance report. CAZ-AVI was evaluated as first-line treatment compared against meropenem, second-line treatment with colistin + tigecycline was used for both arms. Pathogen-specific resistance and effectiveness rates for each antibiotic were sourced from a mix of the REPROVE trial, the literature, a report from the Taiwan CDC, or KOL opinion. The model considered costs for antibiotics, hospitalizations, and recurrence, which were localized to Taiwan. Costs and benefits were discounted at 3%, over the 5-year time horizon, and the model took the perspective of the Ministry of Health and Welfare (MoHW). Compared to meropenem arm, the CAZ-AVI was associated with higher incremental costs (NT$82,856), and quality-adjusted life years (QALYs) (0.06) resulting in an incremental cost-effectiveness ratio of NT$1,328,745 per QALY gained. Incremental total costs were primarily driven by higher costs associated with antibiotics (NT$87,073). However, a decrease in incremental hospitalization costs of NT$4,216 was observed. CAZ-AVI reduced the percentage of patients resistant to first-line therapy and mortality by 6.84%, and 1.02%, respectively. The percentage of patients with overall clinical cure increased by 2.56% in the CAZ-AVI arm compared to the meropenem arm. CAZ-AVI was cost-effective as a first-line treatment for patients with HAP (incl. VAP) in Taiwan.