The Acceptance of Indirect Treatment Comparison Methods in Oncology by Health Technology Assessment Agencies in England, France, Germany, Italy, and Spain.

INTRODUCTION: Randomized controlled trials (RCTs) are the gold standard when comparing treatment effectiveness, and Health Technology Assessment (HTA) agencies state a clear preference for such direct comparisons. When these are not available, an indirect treatment comparison (ITC) is an alternative option. The objective of this study was to assess the acceptance of ITC methods by HTA agencies across England, France, Germany, Italy, and Spain, using oncology cases for a homogeneous sample of HTA evaluations. METHODS: The study was conducted on the PrismAccess database in May 2021 to retrieve HTA evaluation reports for oncology treatments for solid tumors, in which an ITC was presented. The analysis was restricted to HTA evaluation reports published between April 2018 and April 2021 in England, France, Germany, Italy, and Spain. Identified HTA evaluation reports were screened and reviewed by two independent reviewers. For each ITC presented, the methodology and its acceptance by the HTA agency were analyzed. RESULTS: Five hundred and forty-three HTA evaluation reports were identified, of which 120 (22%) presented an ITC. This proportion was the highest in England (51%) and lowest in France (6%). The overall acceptance rate of ITC methods was 30%, with the highest in England (47%) and lowest in France (0%). Network meta-analysis (NMA; 23%) was the most commonly used ITC technique, with a 39% acceptance rate overall, followed by Bucher ITC (19%; 43% acceptance rate) and matching-adjusted indirect comparison (13%; 33% acceptance rate). The most common criticisms of the ITC methods from HTA agencies related to data limitations (heterogeneity and lack of data; 48% and 43%, respectively) and the statistical methods used (41%). CONCLUSIONS: The generally low acceptance rate of ITC methods by HTA agencies in oncology suggests that, whilst in the absence of a direct comparison ITCs may provide relevant evidence, this evidence is not widely considered sufficient for the purpose of HTA evaluations. The perception of ITC methods for the purpose of HTA evaluations varies substantially between countries. There is a need for further clarity on the properties of ITC techniques and the assessment of their results as ITC methods continue to evolve quickly and further techniques may become available in the future.

Real-world evidence for steroidal mineralocorticoid receptor antagonists in patients with chronic kidney disease.

BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) were shown to delay chronic kidney disease (CKD) progression in patients with hypertension and/or heart failure (HF) and proteinuria. OBJECTIVE: We conducted a systematic literature review on real-world evidence to identify the literature gaps related to the efficacy and safety outcomes of MRAs administered to CKD patients. RESULTS: A total of 751 records were identified of which, 23 studies (26 publications) were analyzed. Studies included heterogeneous populations, including the overall CKD, CKD and diabetes, CKD and HF, and CKD and a history of cardiovascular disease. Most of the studies were small and non-rigorous, resulting in a notable lack of evidence in these populations. In the overall CKD population, steroidal MRAs resulted in a significant or sustained eGFR reduction but no efficacy in delaying progression to end-stage kidney disease. No cardiovascular protection was found. Results for all-cause mortality and hospitalization for HF were inconsistent; however, the longest follow-up studies indicate similar or lower incidence for spironolactone non-users. Most results consistently reported a higher incidence of hyperkalemia among patients on steroidal MRAs in all CKD stages, and side effects led to high discontinuation rates in the real-world setting. CONCLUSIONS: Despite the limited availability of evidence on the effectiveness and safety of steroidal MRAs in CKD patients and subgroups with diabetes, HF or history of cardiovascular disease, MRAs were shown to have a limited effect on renal and cardiovascular outcomes. Gaps in the evidence regarding the efficacy and safety of MRAs are particularly relevant in diabetic CKD patients; therefore, further research is warranted.

Validation of the FINE-CKD model for future health technology assessments for finerenone in patients with chronic kidney disease and type 2 diabetes.

BACKGROUND: The FINE-CKD model was developed to estimate the cost-effectiveness of finerenone in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). OBJECTIVE: To perform internal and external validation by comparing the model estimates with trial results and outcomes from other models. METHODS: Incidence rates from trials were compared with the model predictions. Statistical tests were then performed to assess whether modeled event rates aligned with trial observations. A cross-validation was also performed using the online version of the SHARP CKD-Cardiovascular Disease (SHARP CKD-CVD) model, with population characteristics from the finerenone trials analyzed. Where no finerenone data were available, the default SHARP CKD-CVD values were used. Comparison of the results considered the ranges from both models. RESULTS: The outcomes of the FINE-CKD model reflect the event rates observed in the trials. Based on the results of the statistical tests, the hypothesis of no difference between observed and modeled events cannot be rejected for any of the outcomes. The results of the FINE-CKD model are within the ranges from the SHARP CKD-CVD model. Disease progressions align across the models; however, incident kidney failure events in the SHARP CKD-CVD model were higher. This can be explained by simulation of more severely affected patients in the SHARP CKD-CVD model. CONCLUSIONS: This study demonstrates that the FINE-CKD model adequately reflects the clinical data and provides reliable extrapolation relative to the existing predictive tools while also being conservative in its approach.

Public health impact of COVID-19 in French ambulatory patients with at least one risk factor for severe disease.

Background: Quantification of COVID-19 burden may be useful to support the future allocation of resources. Objective: To evaluate the public health impact of COVID-19 in French ambulatory patients with at least one risk factor for severe disease. Study design: A Markov model was used to estimate life years, costs, number of hospitalisations, number of deaths and long/prolonged COVID forms over a time horizon of 2 years. The hospitalisation probabilities were derived from an early access cohort, and the hospitalisation stay characteristics were derived from the French national hospital discharge database. Several scenario analyses were conducted. Results: The number of hospitalisations reached 256 per 1,000 patients over the acute phase (first month of simulation), and 382 per 1,000 patients over 2 years. The number of deaths was 37 per 1,000 patients, and the number of long/prolonged COVID forms reached 407 per 1,000 patients. These translated into a reduction of 0.7 days of life per patient in the first month, with an associated cost of €1,578, and a reduction of 27 days of life over the time horizon, with an associated cost of €4,280. The highest burden was observed for patients over 80 years old, and those not vaccinated. The scenarios with a less severe situation or new treatments available showed a non-negligible burden reduction. Conclusion: This study allowed us to quantify the considerable burden related to COVID-19 in infected patients, with at least one risk factor for severe form. Strategies with the ability to substantially reduce this burden in France are urgently required.

Real-world cost-effectiveness analysis of NOACs versus VKA for stroke prevention in Spain.

AIMS: A Markov model was adapted to assess the real-world cost-effectiveness of rivaroxaban, dabigatran and apixaban. Each of these non-vitamin K antagonist oral anticoagulants was compared with vitamin K antagonist for stroke prevention in patients with non-valvular atrial fibrillation in Spain. METHODS: All inputs were derived from real-world studies: baseline patient characteristics, clinical event rates, as well as persistence rates for the vitamin K antagonist treatment option. A meta-analysis of real-world studies provided treatment effect and persistence data for rivaroxaban, dabigatran and apixaban, each compared with vitamin K antagonist therapy. The model considered 3-month cycles over a lifetime horizon. The model outcomes included different costs, quality-adjusted life years and life-years gained. Sensitivity analyses were performed to test the robustness of the model. RESULTS: When compared with vitamin K antagonist, rivaroxaban incurred incremental costs of €77 and resulted in incremental quality-adjusted life years of 0.08. The incremental cost per quality-adjusted life year was €952. For the same comparison, the incremental cost per quality-adjusted life year for dabigatran was €4,612. Finally, compared with vitamin K antagonist, the incremental cost per quality-adjusted life year for apixaban was €32,015. The sensitivity analyses confirmed the robustness of the base case results. The probabilities to be cost-effective versus vitamin K antagonist were 94%, 86% and 35%, respectively, for rivaroxaban, dabigatran and apixaban, considering a willingness-to-pay threshold of €22,000 per quality-adjusted life year gained, based on a cost-effectiveness study of the Spanish National Health System. CONCLUSION: These results suggest that rivaroxaban and dabigatran are cost-effective versus vitamin K antagonist for stroke prevention in non-valvular atrial fibrillation, from the Spanish National Health System perspective.

FINE-CKD model to evaluate economic value of finerenone in patients with chronic kidney disease and type 2 diabetes.

BACKGROUND: Chronic kidney disease (CKD) is a progressive and irreversible disease often associated with type 2 diabetes (T2D). CKD is associated with an elevated risk of cardiovascular (CV) events, increased mortality, and diminished quality of life. Finerenone is a new treatment for patients with CKD and T2D that delays CKD progression and reduces CV complications. OBJECTIVE: To describe the approach and structure of a costeffectiveness model for finerenone for patients with CKD and T2D and compare it with existing economic models in CKD. METHODS: A de novo cost-effectiveness model (FINE-CKD model), reflective of FIDELIO-DKD results, was developed for finerenone. The FINE-CKD model was designed and implemented in accordance with published guidance on modeling and was developed with input from economic and clinical experts. The final model approach was evaluated against existing modeling structures in CKD identified through a systematic literature review. RESULTS AND CONCLUSIONS: The FINE-CKD model structure follows recommended modeling guidelines and has been designed in accordance with the best practices of modeling in CKD, while also incorporating important features of the FIDELIO-DKD design and results. The approach is consistent with the published literature, ensuring transparency and minimizing uncertainty that can arise from unnecessary complexity. The FINE-CKD model allows for reliable assessment of benefits and costs related to the use of finerenone in patients with CKD and T2D, and it is a reliable assessment of cost-effectiveness.

Targeted literature review of the burden of illness in patients with chronic kidney disease and type 2 diabetes.

OBJECTIVES: Chronic kidney disease (CKD) is increasingly prevalent among patients with type 2 diabetes (T2D). CKD is associated with increased mortality rates, clinical and humanistic burden, and substantial health care costs in the T2D population. The objective of this review was to summarize the burden of illness among patients with CKD and T2D, including the profile of patients, incidence, prevalence, mortality, progression, diagnosis and screening rates, and cardiovascular (CV) events. METHODS: A targeted literature review of published studies was conducted using Embase; Medline; Medline In-Process Citations, Daily Update, and Epub Ahead of Print; Igaku Chuo Zasshi databases; and 7 websites. Methods recommended by the Cochrane collaboration handbook, the Centre for Reviews and Dissemination, and the Joanna Briggs Institute critical appraisal checklist were employed. RESULTS: A total of 1290 full-text articles were reviewed for eligibility and 73 were included in this analysis. Patient profiles indicated older age was associated with more severe disease and number of comorbidities. The definition of kidney disease varied between studies reporting incidence and prevalence, with reported values up to 37.0% and 43.5% for incidence and prevalence, respectively. CKD among patients with T2D contributed to higher mortality rates. Higher disease progression rates were associated with higher albuminuria and lower estimated glomerular filtration rate levels. The available literature suggested annual screening rates for CKD declined over time. CV events were reported to have a substantial effect on morbidity and resource use. CONCLUSIONS: This review highlights the burden of CKD among patients with T2D and underscores a need for new treatment alternatives to reduce the burden of disease.

Health economic evaluation of gene replacement therapies: methodological issues and recommendations.

Objective: To provide recommendations for addressing previously identified key challenges in health economic evaluations of Gene Replacement Therapies (GRTs), including: 1) the assessment of clinical effectiveness; 2) the valuation of health outcomes; 3) the time horizon and extrapolation of effects beyond trial duration; 4) the estimation of costs; 5) the selection of appropriate discount rates; 6) the incorporation of broader elements of value; and 7) affordability. Methods: A literature review on economic evaluations of GRT was performed. Interviews were conducted with 8 European and US health economic experts with experience in evaluations of GRT. Targeted literature reviews were conducted to investigate further potential solutions to specific challenges. Recommendations: Experts agreed on factors to be considered to ensure the acceptability of historical cohorts by HTA bodies. Existing prospective registries or, if not available, retrospective registries, may be used to analyse different disease trajectories and inform extrapolations. The importance of expert opinion due to limited data was acknowledged. Expert opinion should be obtained using structured elicitation techniques. Broader elements of value, beyond health gains directly related to treatment, can be considered through the application of a factor to inflate the quality-adjusted life years (QALYs) or a higher cost-effectiveness threshold. Additionally, the use of cost-benefit analysis and saved young life equivalents (SAVE) were proposed as alternatives to QALYs for the valuations of outcomes of GRT as they can incorporate broader elements of value and avoid problems of eliciting utilities for paediatric diseases. Conclusions: While some of the limitations of economic evaluations of GRT are inherent to limited clinical data and lack of experience with these treatments, others may be addressed by methodological research to be conducted by health economists.

Cultural Variations in Public Beliefs about Mental Disorders: A Comparison between Tunisia and Germany.

BACKGROUND: In recent years there is a growing interest in public beliefs about mental disorders. Numerous representative population-based studies have been conducted around the globe, also in European countries bordering on the Mediterranean Sea. However, relatively little is known about public beliefs in countries in Northern Africa. OBJECTIVE: To fill this gap by comparing public beliefs about mental disorders in Tunisia and Germany, focusing on causal beliefs, help-seeking recommendations and treatment preferences. METHODS: Representative national population-based surveys have been conducted in Tunisia in 2012 (N = 811) and in Germany in 2011 (N = 1852), using the same interview mode and the same fully structured interview starting with a vignette depicting a person suffering from either schizophrenia or depression. RESULTS: In Tunisia, the public was more likely to adopt psychosocial and to reject biogenetic explanations than in Germany. Correspondingly, psychological treatments were more frequently recommended and biological ones more frequently advised against. There was also a strong inclination to share religious beliefs and to recommend seeking religious advice. Tunisians tended much more than Germans to hold moralistic views and to blame the afflicted person for his or her illness. In Tunisia, the public tended less to differentiate between schizophrenia and depression than in Germany. CONCLUSION: Marked differences between Tunisia and Germany exist in public beliefs about the causes of mental disorders and their treatment, which correspond to differences in cultural orientations prevailing in these countries. Mental health professionals need to be sensitive to the particular cultural context in which they operate, in order to be able to reach those they intend to care for.

Real-world cost-effectiveness of rivaroxaban and apixaban vs VKA in stroke prevention in non-valvular atrial fibrillation in the UK.

BACKGROUND: Morbidity and mortality associated with non-valvular atrial fibrillation (NVAF) imposes a substantial economic burden on the UK healthcare system. OBJECTIVES: An existing Markov model was adapted to assess the real-world cost-effectiveness of rivaroxaban and apixaban, each compared with a vitamin K antagonist (VKA), for stroke prevention in patients with NVAF from the National Health Service (NHS) and personal and social services (PSS) perspective. METHODS: The model considered a cycle length of 3 months over a lifetime horizon. All inputs were drawn from real-world evidence (RWE): baseline patient characteristics, clinical event and persistence rates, treatment effect (meta-analysis of RWE studies), utility values and resource use. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: The incremental cost per quality-adjusted life year was £14,437 for rivaroxaban, and £20,101 for apixaban, compared with VKA. The probabilities to be cost-effective compared with VKA were 90% and 81%, respectively for rivaroxaban and apixaban, considering a £20,000 threshold. In both comparisons, the results were most sensitive to clinical event rates. CONCLUSIONS: These results suggest that rivaroxaban and apixaban are cost-effective vs VKA, based on RWE, considering a £20,000 threshold, from the NHS and PSS perspective in the UK for stroke prevention in patients with NVAF. This economic evaluation may provide valuable information for decision-makers, in a context where RWE is more accessible and its value more acknowledged.

Social Preferences for Orphan Drugs: A Discrete Choice Experiment Among the French General Population.

Objectives: While several authors have suggested using a multi-criteria approach for orphan drug assessment and proposed lists of determinants of orphan drug value, studies on social preferences regarding these determinants remain limited. The current study aimed to identify preferences of the French general population regarding attributes characterizing the value of orphan drugs in a discrete choice experiment. Methods: The list of attributes was formed based on a literature search and was refined through expert interviews, a focus group, and a pilot study. The final list included nine attributes: disease-associated disability, disease-associated mortality, number of patients, availability of alternative treatments, treatment impact on disease disability, treatment impact on mortality, treatment safety, uncertainty around therapeutic effect, and annual treatment cost per patient. Members of the General Public were presented with 12 choice sets containing two drug profiles described according to the attributes and an option to fund neither of these treatments. The questionnaire was disseminated online. A conditional logit model with random effects was used to estimate the weight of each attribute. Results: A total of 958 persons participated in the study (48.7% male, mean age: 47.5 years). All attributes except for disease-associated disability had a statistically significant influence on the choices made by participants. The attribute with the highest weight was treatment impact on mortality (p < 0.0001), followed by uncertainty around therapeutic effect (p < 0.0001). The direction of results was generally consistent with intuition: patients preferred a drug with a larger impact on mortality, a larger impact on disability, with mild or no adverse events, with less uncertainty. Although patients appeared to prefer drugs with a lower budget impact, the relationship between patient preferences and costs was more complex. Conclusions: Preferences of the general public between orphan drugs are mostly driven by the impact on mortality and the degree of certainty regarding the available evidence.

Use of real-world evidence in meta-analyses and cost-effectiveness models.

Real-world evidence (RWE) provides external validity, supplementing and enhancing the randomized controlled trial data with valuable information on patient behaviors and outcomes, turning efficacy and safety results into real-world effectiveness and risks, but the use of RWE is associated with challenges. The objectives of this communication were to (1) summarize all guidance on how to conduct an RWE meta-analysis (MA) and how to develop an RWE cost-effectiveness model, (2) to describe our experience, challenges faced and solutions identified, (3) to provide recommendations on how to conduct such analyses. No formal guidelines on how to conduct an RWE MA or to develop an RWE cost-effectiveness model were identified. Using the context of non-vitamin K antagonist oral anticoagulants in stroke prevention in atrial fibrillation, we conducted an RWE MA, after having identified sources of uncertainty. We then implemented the results in an RWE cost-effectiveness model, defined as a model where all inputs come from RWE, including all parameters related to treatment effect. Based on challenges faced, our first recommendation relates to the necessity of conducting sensitivity analyses, either based on clinical or methodological considerations. Our second recommendation is the need for extensive collaboration with a wide range of experts, during the development of the analyses protocols, the implementation of the analyses and the interpretation of the results. RWE may address a number of gaps related to the treatment effect, and RWE economic evaluations for the treatment effect can provide extremely valuable insights into real-world economic value of interventions. As the increased recognition of the value of RWE could influence health technology assessment decision, and current practices, this communication supports the urgent need of more formal guidelines.

Cost-Effectiveness of Coronary and Peripheral Artery Disease Antithrombotic Treatments in Finland.

INTRODUCTION: Currently, 15-20% of individuals with coronary artery disease (chronic coronary syndrome [CCS]) or peripheral artery disease (PAD) receiving routine treatment experience cardiovascular events (CVEs) within 3-4 years. Using PICOSTEPS (Patients-Intervention-Comparators-Outcomes-Setting-Time-Effects-Perspective-Sensitivity analysis) reporting, we evaluated the cost-effectiveness of recently approved rivaroxaban 2.5 mg twice daily in combination with acetylsalicylic acid 100 mg daily (RIV + ASA) for the prevention of CVEs among Finns with CCS or symptomatic PAD. METHODS: Myocardial infarction, ischemic stroke, intracranial hemorrhage, acute limb ischemia, amputations, major extracranial bleeding, venous thromboembolism, and cardiovascular deaths were modeled in a Markov model examining a cohort of patients with CCS or symptomatic PAD. Relative effects of the intervention (RIV + ASA) and comparator (ASA) were based on the COMPASS trial. The primary outcome was 3%/year discounted incremental cost-effectiveness ratio (ICER), defined as cost (2019 euros) per quality-adjusted life year (QALY) gained in the Finnish setting over a lifetime horizon. In addition to nonfatal and fatal CVEs, the effects factored Finnish non-CVE mortality, quality of life, and direct costs from a public payer perspective. Disaggregated costs and QALYs, costs per life year gained (LYG), and ischemic strokes avoided, net monetary benefit (NMB), expected value of perfect information (EVPI), economic value-added (EVA), cost-effectiveness table, and acceptability frontier were examined. Probabilistic and deterministic sensitivity analyses were conducted. RESULTS: In the deterministic comparison with ASA over a lifetime horizon, RIV + ASA resulted in a benefit of 0.404 QALYs and 0.474 LYGs for an additional cost of €3241, resulting in an ICER of €8031/QALY. The probabilistic ICER was €4313/QALY (EVPI €1829/patient). RIV + ASA had positive NMB (€8791/patient), low EVPI (€88/patient), high EVA (€8703/patient), and 91% probability of cost-effectiveness using the willingness-to-pay of €25,254/QALY. The primary result was conservative and robust for RIV + ASA. CONCLUSION: RIV + ASA was a cost-effective treatment alternative compared with ASA in patients with CCS or symptomatic PAD in Finland.

Finland lacks published evidence on the cost-effectiveness of approved interventions for the prevention of cardiovascular events among individuals with chronic coronary syndrome (stable coronary artery disease) or symptomatic peripheral artery disease at risk of cardiovascular complications. Rivaroxaban 2.5 mg twice daily plus acetylsalicylic acid 100 mg once daily is indicated and reimbursed in Finland for the prevention of cardiovascular events for patients with stable coronary artery disease or symptomatic peripheral artery disease. We assessed the effectiveness and costs of treatment with rivaroxaban plus acetylsalicylic acid in comparison with treatment with acetylsalicylic acid. That is, we examined whether rivaroxaban is cost-effective when prescribed in combination with acetylsalicylic acid.Cardiovascular events with their associated costs and impact on quality of life were modeled over the lifetime of patients. The main effectiveness outcome was quality-adjusted life years (modeled survival multiplied by the expected quality of life), and costs included those relevant to the Finnish public payer in 2019. Extensive sensitivity analyses were carried out to evaluate the impacts of different model inputs and rationale.Rivaroxaban plus acetylsalicylic acid had high probability of being cost-effective, compared with acetylsalicylic acid. By valuing quality-of-life benefit with a plausible willingness-to-pay, net cost savings of €8791 per patient could be gained or economic value added by €8703 per patient if rivaroxaban was used.

Real-world cost-effectiveness of rivaroxaban compared with vitamin K antagonists in the context of stroke prevention in atrial fibrillation in France.

OBJECTIVE: The objective was to assess the real-world cost-effectiveness of rivaroxaban, versus vitamin K antagonists (VKAs), for stroke prevention in patients with atrial fibrillation (AF) from a French national health insurance perspective. METHODS: A Markov model was developed with a lifetime horizon and cycle length of 3 months. All inputs were drawn from real-world evidence (RWE) studies: data on baseline patient characteristics at model entry were obtained from a French RWE study, clinical event rates as well as persistence rates for the VKA treatment arm were estimated from a variety of RWE studies, and a meta-analysis provided comparative effectiveness for rivaroxaban compared to VKA. Model outcomes included costs (drug costs, clinical event costs, and VKA monitoring costs), quality-adjusted life-years (QALY) and life-years (LY) gained, incremental cost per QALY, and incremental cost per LY. Sensitivity analyses were performed to test the robustness of the model and to better understand the results drivers. RESULTS: In the base-case analysis, the incremental total cost was €714 and the total incremental QALYs and LYs were 0.12 and 0.16, respectively. The resulting incremental cost/QALY and incremental cost/LY were €6,006 and €4,586, respectively. The results were more sensitive to the inclusion of treatment-specific utility decrements and clinical event rates. CONCLUSIONS: Although there is no official willingness-to-pay threshold in France, these results suggest that rivaroxaban is likely to be cost-effective compared to VKA in French patients with AF from a national insurance perspective.

Health economic evaluation of rivaroxaban in the treatment of patients with chronic coronary artery disease or peripheral artery disease.

AIMS: In the COMPASS trial, rivaroxaban 2.5 mg twice daily (bid) plus acetylsalicylic acid (ASA) 100 mg once daily (od) performed better than ASA 100 mg od alone in reducing the rate of cardiovascular disease, stroke, or myocardial infarction (MI) in patients with coronary artery disease (CAD) and peripheral artery disease (PAD). A Markov model was developed to assess the cost-effectiveness of rivaroxaban plus ASA vs. ASA alone over a lifetime horizon, from the UK National Health System perspective. METHODS AND RESULTS: The base case analysis assumed that patients entered the model in the event-free health state, with the possibility to experience ≤2 events, transitioning every three-month cycle, through acute and post-acute health states of MI, ischaemic stroke (IS), or intracranial haemorrhage (ICH), and death. Costs, quality-adjusted life-years (QALYs), life years-all discounted at 3.5%-and incremental cost-effectiveness ratios (ICERs) were calculated. Deterministic and probabilistic sensitivity analyses were conducted, as well as scenario analyses. In the model, patients on rivaroxaban plus ASA lived for an average of 14.0 years with no IS/MI/ICH, and gained 9.7 QALYs at a cost of £13 947, while those receiving ASA alone lived for an average of 12.7 years and gained 9.3 QALYs at a cost of £8126. The ICER was £16 360 per QALY. This treatment was cost-effective in 98% of 5000 iterations at a willingness-to-pay threshold of £30 000 per QALY. CONCLUSION: This Markov model suggests that rivaroxaban 2.5 mg bid plus ASA is a cost-effective alternative to ASA alone in patients with chronic CAD or PAD.

Systematic review of utility values used in the pharmacoeconomic evaluations for schizophrenia: implications on cost-effectiveness results.

Background and Objectives: Utility elicitation studies for schizophrenia generate different utility values for the same health states. We reviewed utility values used in schizophrenia pharmacoeconomic evaluations and evaluated the impact of their selection on the incremental cost-effectiveness ratio (ICER). Methods: A systematic search was performed in Medline and Embase. Health state definitions, associated utility values, elicitation studies, and value selection processes were extracted. Sets of utility values for all schizophrenia health states were used in a cost-effectiveness model to evaluate the ICER. Results: Thirty-five cost-utility analyses (CUAs) referring to 11 utility elicitation studies were included. The most frequent health states were 'stable' (28 CUAs, 7 utility elicitation studies, 10 values, value range 0.650-0.919), 'relapse requiring hospitalisation' (18, 5, 7, 0.270-0.604), 'relapse not requiring hospitalisation' (18, 5, 10, 0.460-0.762), and 'relapse only' (10, 5, 6, 0.498-0.700). Seventeen sets of utility values were identified with difference in utility values between relapse and stable ranging from -0.358 to -0.050, resulting in ICERs ranging from -56.2% to +222.6% from average. Conclusion: The use of utility values for schizophrenia health states differs among CUAs and impacts on the ICER. More rigorous and transparent use of utility values and sensitivity analysis with different sets of utility values are suggested for future CUAs.

Impact of methodological choices on a meta-analysis of real-world evidence comparing non-vitamin-K antagonist oral anticoagulants with vitamin K antagonists for the treatment of patients with non-valvular atrial fibrillation.

Objective: The aim of this study was to investigate the impact of methodological choices in a meta-analysis of real-world evidence (RWE) comparing three non-vitamin-K antagonist oral anticoagulants with vitamin K antagonists (VKAs) for the treatment of patients with non-valvular atrial fibrillation (NVAF). Methods: The meta-analysis was based on a systematic review of RWE studies enrolling incident and prevalent patients aged ≥18 years with NVAF and receiving either rivaroxaban, dabigatran, apixaban or a VKA. Five different scenarios were considered to explore the impact of the initial meta-analysis assumptions: (1) using studies that involved only incident patients; (2) excluding studies that only reported crude values and did not consider any adjustment; (3) including all studies independently of possible database overlap; (4) using studies with data on different dosages for rivaroxaban and dabigatran; and (5) assigning quality weights to studies to assess quality of reporting. These scenarios were run on three outcomes: ischemic stroke (IS), myocardial infarction (MI) and intracranial hemorrhage (ICH). Results: Across all scenarios, rivaroxaban was associated with significantly lower risks of IS and ICH than VKAs. In most scenarios, dabigatran was associated with significantly lower risks of IS and ICH. In all scenarios, apixaban was associated with a significantly lower risk of ICH. Conclusions: Sensitivity analyses showed the impact of similar assumptions was different depending on the outcome and the drug considered. The development of recommendations and guidelines for the inclusion of RWE in meta-analyses could prove useful in evaluating the effectiveness of health care interventions.

Number needed to treat based on real-world evidence for non-vitamin K antagonist oral anticoagulants versus vitamin K antagonist oral anticoagulants in stroke prevention in patients with non-valvular atrial fibrillation.

Aims: Non-vitamin K antagonist oral anticoagulants (NOACs) and vitamin K antagonists (VKAs) are used to prevent stroke in patients with atrial fibrillation (AF). This paper aimed to evaluate the clinical efficacy and safety of NOACs when compared to VKAs by calculating the number needed to treat (NNT) at 2 years using incidence rates and hazard ratios (HRs) derived from a meta-analysis of studies conducted in real-world settings. Materials and methods: HRs were sourced from a published systematic literature review and a meta-analysis of real-world evidence on the use of NOACs vs VKAs. Rivaroxaban, dabigatran, and apixaban vs VKAs were investigated. The efficacy outcomes included: a composite of ischaemic stroke and systemic embolism (IS/SE), ischaemic stroke (IS), and all-cause mortality. The safety analysis assessed major bleeding and intracranial haemorrhage (ICH). Results: Superiority of NOACs vs VKAs was observed in 10/15 comparisons. Treating patients with rivaroxaban and dabigatran was associated with a reduced risk of IS and all-cause mortality compared to VKAs, with one death prevented every 22 and 32 patients, respectively, and one IS prevented every 206 and 166 patients, respectively. Rivaroxaban was significantly associated with a reduced risk of IS/SE compared to VKA (NNT: 107). No significant differences were observed between apixaban and VKAs. Dabigatran and apixaban were associated with a reduced risk of major bleeding compared to VKA (NNT: 59 and 38, respectively). No significant difference was observed between rivaroxaban and VKAs regarding major bleeding. Rivaroxaban, dabigatran, and apixaban were significantly associated with a reduced risk of ICH (NNT: 205, 115, and 108, respectively). Limitations: Heterogeneity in definitions of major bleeding across studies. Conclusions: The NNT calculation, when approached and interpreted properly, is a practical measure of the effectiveness of a treatment. The calculation based on HRs showed that NOACs are safe and effective alternatives to VKAs in real life.

Cost-effectiveness analyses using real-world data: an overview of the literature.

Objectives: Real-world evidence (RWE) may provide good estimates of absolute event probabilities and costs in patients in actual clinical practice, but their use in decision-analytic models poses many challenges. A literature review based on a systematic search was conducted to summarize the limitations of using RWE in decision-analytic modeling reported in the literature, but also to identify existing recommendations about real-world modeling. Methods: A literature search was performed on Medline and Embase databases, as well as relevant websites. No restrictions in language or geographical scope were imposed. Results: A total of 14 references were included. RWE is recognized as a valuable source of data for market access and reimbursement, and as a complement to clinical trial evidence for treatment pathways, resource use, long-term natural history, and effectiveness. The main limitations identified in the literature were: confounding bias, missing data, lack of accurate data related to drug exposure and outcomes, errors during the record-keeping process, protection of private data, and insufficient numbers of patients. Although most submission guidelines recognized the potential biases associated with RWE, guidance on the appropriate methods to deal with these biases, and approaches to review different relevant evidence to inform model development, were scarce. Several initiatives have attempted to provide guidance on the use of RWE in decision-modeling. Conclusions: RWE is likely to be particularly valuable for informing healthcare policy-makers when formulating appropriate treatment pathways, encouraging the optimal allocation of scarce resources, and improving aggregate patient outcomes. However, little guidance is available on the relative merits of using efficacy and/or effectiveness evidence in Health Technology Appraisal submissions. Further research is needed to better understand these methods and their potential applications in a broader range of scenarios and simulation studies, and their impact on economic modeling.

Meta-analysis of real-world evidence comparing non-vitamin K antagonist oral anticoagulants with vitamin K antagonists for the treatment of patients with non-valvular atrial fibrillation.

Introduction: Numerous real-world studies have compared non-vitamin K antagonist oral anticoagulants (NOACs) with vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF). A meta-analysis was performed to synthesize the available evidence. Methods: Systematic searches were performed through 12/2016 to identify non-randomized NVAF studies comparing NOACs with VKAs, and reporting effectiveness, safety, or persistence. Results: Of 562 citations identified, 49, 79, and 18 compared rivaroxaban, dabigatran, and apixaban, respectively, with VKAs and were included. Compared with VKAs, rivaroxaban was associated with a reduced risk of ischemic stroke (IS) (hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.75-0.93), intracranial haemorrhage (ICH) (HR = 0.69, 95% CI = 0.52-0.90), and non-persistence (HR = 0.62, 95% CI = 0.60-0.65). Dabigatran was associated with a significantly lower risk of IS (HR = 0.80, 95% CI = 0.65-0.98) and ICH (HR = 0.45, 95% CI = 0.36-0.58), but not for non-persistence (HR = 0.91, 95% CI = 0.53-1.55), compared with VKAs. Apixaban was associated with a lower risk of ICH than VKAs (HR = 0.41, 95% CI = 0.28-0.60), but was not different to VKAs in terms of IS (HR = 1.01, 95% CI = 0.87-1.17) or non-persistence (HR = 1.08, 95% CI = 0.81-1.45). Conclusion: NOACs appear to be at least as effective and safe as VKAs for stroke prevention in patients with NVAF.