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Objectives: Using the case study of patisiran and inotersen, we conducted a narrative comparative analysis of the health technology assessment (HTA) agency appraisals of these two first-in-class transthyretin gene silencers, which represent exceptional advances in the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis, a rare and multisystemic disease. Despite the impact of each product on the treatment landscape, the majority of HTAs are only considered standard of care as a comparator, resulting in a void of information and limited comprehension of the clinical and pharmacoeconomic differences between the two treatments. Methods: A search was conducted internationally for HTA reports, and only instances where assessment decisions for both treatments were publicly available were included in the present analysis. The HTA reports were analyzed broadly for the assessment of clinical and pharmacoeconomic evidence. Only economic models considering both patisiran and inotersen were included in this analysis. Results: A total of nine agencies with public assessment reports for both treatments were identified. HTA agency assessments for both treatments were essentially positive; however, differences were noted in the final recommendations, place in treatment or reimbursed indications, and in the narrative of the evaluations. Only the Canadian Agency for Drugs and Technologies in Health (CADTH) assessment for patisiran evaluated an economic model comparing the two treatments. Conclusions: The differences summarized in this comparative analysis may provide a more comprehensive overview of the two treatments.

BackgroundAvapritinib, a potent inhibitor of KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine kinases, has demonstrated unprecedented clinical activity in PDGFRA D842V-mutant gastrointestinal stromal tumors (GIST).MethodsThis retrospective analysis compared efficacy of avapritinib in patients enrolled in the NAVIGATOR phase 1 trial (NCT02508532) with the efficacy of other tyrosine kinase inhibitors (TKIs) in patients with unresectable/metastatic PDGFRA D842V-mutant GIST enrolled in a retrospective natural history study (Study 1002). The primary endpoint was overall survival (OS) from the start of reference treatment (avapritinib for NAVIGATOR patients or first-line TKI for treatment of unresectable/metastatic GIST for Study 1002 patients); the secondary endpoint was progression-free survival (PFS). Adjusted Kaplan–Meier survival curves were compared by Cox regression.ResultsFifty-six (NAVIGATOR) and 19 (Study 1002) patients with PDGFRA D842V-mutant GIST were evaluated; of the 56 patients from NAVIGATOR, a subgroup of patients treated with either 300 mg (recommended phase 2 dose) or 400 mg (maximum tolerated dose) avapritinib starting dose (n = 38) were analyzed separately. Patient characteristics were adjusted for imbalances by propensity score between the study groups. Inverse probability of treatment weighting-adjusted Kaplan–Meier analysis of OS showed median OS was not reached for NAVIGATOR patients treated with any of the avapritinib doses tested and was 12.6 months for Study 1002 patients; OS rate at 6/48 months was 100%/63% in NAVIGATOR and 56%/17% in Study 1002 (P = 0.0001). In the 300/400 mg subgroup, adjusted OS rates at 6/36 months were 100%/73 and 68%/20% in Study 1002 (P = 0.0016). Adjusted median PFS was 29.5 months in NAVIGATOR and 3.4 months in Study 1002.ConclusionsIn this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST.Trial registrationThe NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier:NCT02508532.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. MS is considered incurable; however, disease treatment has advanced significantly over the past several decades with the introduction of disease-modifying therapies (DMTs). The current study reviewed the cost-effectiveness analyses of DMTs in relapsing–remitting MS (RRMS) patients. A systematic literature search of bibliographic databases was conducted to identify economic evaluations published after 2007. The relevant population, intervention, comparators, outcomes, and study design (PICOS) were considered. The outcomes of interest were incremental cost-effectiveness ratios (ICERs), net monetary benefits, incremental benefits, and incremental costs. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement was used to assess the reporting quality of published studies. A total of 1370 potentially relevant citations were identified, of which 33 published articles and four Health Technology Assessment (HTA) reports prepared for the UK were included in the final analysis. Almost all studies were based on a health economic model and considered RRMS as the phase of disease at study entry. The studies were conducted in 10 different countries, with approximately 50% based in the US. Study outcomes were rarely comparable due to the different settings, input data, and assumptions. Even within the same country, the discrepancy between study criteria was considerable. The compliance with reporting standards of the CHEERS statement was generally high. Internationally, a large number of health economic assessments of DMTs in RRMS were available, yielding difficult to compare, and at times conflicting, results.

This study explored the use of a value-based pricing approach for the new calcimimetic etelcalcetide indicated for the treatment of secondary hyperparathyroidism (SHPT) in patients receiving hemodialysis. It used the US payer perspective and applied the cost-effectiveness framework. Because etelcalcetide is an intravenous therapy that can be titrated for individual patients, and because its utilization is yet to be assessed in real world settings, a range of plausible doses were estimated for etelcalcetide to define a range of prices. These were either in relation to the existing oral calcimimetic cinacalcet or compared to no calcimimetic treatment.The value-based price of etelcalcetide was determined via a Markov model. This model combined data from the etelcalcetide trials and previously published cost-effectiveness models in SHPT, and allowed extrapolation of treatment effects on mortality, cardiovascular events, fracture, and parathyroidectomy. Several dosing scenarios were explored covering the dose ranges of 30.0-64.18 mg per day for cinacalcet and 1.07-3.11 mg per day for etelcalcetide. These included the mean dose from the etelcalcetide trials, the preliminary defined daily dose, and the expected most common dose in real world. An acceptable price range for etelcalcetide was assessed by comparing the incremental cost-effectiveness ratios obtained with the willingness-to-pay threshold range of $100,000-$300,000/quality-adjusted life-years.Cost-effectiveness analysis supported value-based prices for etelcalcetide ranging from $21.15-$49.97/mg vs cinacalcet, and $13.79-$119.45/mg vs no calcimimetics.There is uncertainty around what the real-world dosing will be for etelcalcetide. Another important nuance is that no studies have examined etelcalcetide effects on hard outcomes and, therefore, this modeling exercise relied on an extrapolation approach.This cost-effectiveness analysis, including scenarios to address uncertainties, allowed estimation of a value-based price range to aid reimbursement decisions in the US.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with a very high economic impact. Peginterferon beta-1a is the first approved pegylated interferon beta-1a for the treatment of relapsing-remitting multiple sclerosis (RRMS). Its efficacy and safety were demonstrated in the placebo-controlled ADVANCE trial. A complete path to the assessment of a new health technology requires, in addition to a clinical evaluation, also an economic evaluation. In Italy, two economic evaluations were conducted and recently published. The objective of this article is focused on the two Italian economic analyses in order to describe the methods used, to summarize the main results, and to give a comprehensive picture of the pharmacoeconomic profile of peginterferon beta-1a in Italy in approved indication. The two analyses were conducted to evaluate such profile; the former was a cost-effectiveness analysis, the latter was a budget impact analysis: 1) The cost-effectiveness analysis – developed through a lifetime Markov model – compared peginterferon beta-1a with injectable first-line treatments for RRMS in Italy from the perspective of the Italian National Healthcare Service (NHS) and from the societal perspective. Efficacy data were derived from a published Network Meta-analysis. Unit costs were based on current prices and tariffs, and the published literature. From the Italian NHS perspective, peginterferon beta-1a was dominant in one case, while in all others its incremental cost-effectiveness ratio (ICER) was between €10,580/QALY and €22,023/QALY. From the societal perspective, peginterferon beta-1a was dominant versus every comparator. 2) The budget impact analysis estimated – using a simple decision analytic model from the perspective of the Italian NHS – the financial impact due to the introduction of peginterferon beta-1a on the Italian drug market. The cumulative budget impact over 3 years was a cost saving of approximately €3.1 million. Based on the results of both analyses, the adoption of peginterferon beta-1a for the treatment of RRMS is not only clinically effective, but also economically efficient and financially sustainable from the Italian NHS perspective.

Atrial fibrillation (AF) is the most prevalent form of alteration in cardiac rhythm and is associated with a high economic burden resulting from both clinical consequences and impact on patients’ quality of life. Goals of treatment include symptom control and, in the high-risk patients, the prevention of thromboembolic complications. The advent of novel oral anticoagulant agents (NOACs) has improved the management of patients with non-valvular AF (NVAF) by overcoming limitations associated with traditional oral anticoagulation drugs. NOACs are associated with a lower risk of stroke, systemic embolism, and mortality compared to vitamin K antagonists (VKAs) and with a lower risk of fatal, major, and intracranial bleeding. This supplement aims at sharing the virtuous management model of AF patients in the Local Health Unit Tuscany North-West and promoting the importance of a multidisciplinary management, which involves cardiologists and general practitioners (GPs), not only in terms of clinical outcomes, but also of therapeutic appropriateness and economic sustainability.

Aim In patients with chronic kidney disease (CKD), hyperkalaemia (HK) (potassium level ≥ 5.0 mEq/L) is associated with poor clinical outcomes. This study provides novel insights by comparing management costs of CKD patients with normokalaemia vs those with persistent HK regularly followed in renal clinics in Italy. Methods To this aim, a Markov model over life-time horizon was developed. Time to end-stage renal disease (ESRD) and time to death in CKD patients were derived from an observational multi-centre database including 1665 patients with non-dialysis CKD stage 1-5 under nephrology care in Italy (15 years follow-up). Resource use for CKD and HK management was obtained from the observational database, KDIGO international guidelines, and clinical expert opinion. Results Results showed that patients with normokalaemia vs persistent HK brought an average per patient lifetime cost-saving of €16 059 besides delayed onset of ESRD by 2.29 years and increased survival by 1.79 years with increment in total survival and dialysis-free survival in normokalaemia that decreased from early to advanced disease. Cost-saving related to normokalaemia increased at more advanced CKD; however, it was already evident at early stage (3388.97€ at stage 1-3a). OWSA confirmed cost-saving associated with normokalaemia across all parameter variations. Discussion and conclusion This model is the first to simulate the impact of HK in non-dialysis CKD patients on economic and clinical outcomes using real-world data from nephrology clinics. In these patients, persistent HK results into higher lifetime costs, besides poorer clinical outcomes, that are evident since the early stages of CKD. Maintaining normokalaemia should therefore be of main concern in CKD treatment planning to improve long-term economic and clinical outcomes.

Pegylation is a procedure used for drug development since the 1970s and consists of the conjugation of a polyethylene glycol molecule (PEG) to a drug. PEG has shown to be safe and effective in improving the pharmacokinetic and pharmacodynamic profile of drugs. Recently, a 20 kDa linear chain of PEG was conjugated to interferon beta-1a with the aim to offer a new treatment option to relapsing-remitting multiple sclerosis (RRMS) patients. Due to a prolonged bioavailability, this new drug can be administered less frequently (every two weeks) than the other interferons beta available, thus allowing to hypothesize a better adherence to the treatment, which, in turn, should result in better clinical and economic outcomes. A phase III clinical trial has proven its effectiveness compared to placebo in RRMS patients, as well as a safety profile comparable to that found in other interferon beta preparations. The immunogenicity of this new molecule is < 1%, thus minimizing the suppression or reduction of interferon beta biological activity that could come from the development of Neutralizing Antibodies (NAbs).[Article in Italian]

INTRODUCTION: Disease Modifying Therapies (DMTs) have significantly improved clinical conditions of Relapsing Remitting Multiple Sclerosis (RRMS) patients. However, several unmet needs are still relevant in RRMS. Recently, a new therapy, delayed-release dimethyl-fumarate (DMF; also known as gastro-resistant DMF), has been approved and reimbursed by the Italian Drug Agency (AIFA) for the treatment of RRMS.OBJECTIVE: To compare the cost-effectiveness of DMF vs. pharmacological alternatives indicated for the first-line treatment of RRMS in Italy.METHODS: The analysis was conducted from the perspective of the Italian National Healthcare Service (NHS) and outcomes and costs were evaluated over a 50-year time horizon (equivalent to a lifetime horizon). Both outcomes and costs were discounted at 3.5%. The Markov model estimates the clinical and economic consequences of treating RRMS patients with the following therapeutic options: DMF, interferon (IFN) beta-1a intramuscular (IM); IFN beta-1a subcutaneous (SC) at two different doses, 22 mcg and 44 mcg; IFN beta-1b SC; glatiramer acetate (GA) SC 20 mg; oral teriflunomide. Clinical efficacy data used in this analysis came from an elaboration of the mixed treatment comparison (MTC) already published. According to the Italian NHS perspective, only the following direct costs were considered: pharmacological treatment acquisition, treatment monitoring, relapse management, direct costs associated with disability, adverse event management. Administration costs were assumed equal to €0, because every treatment included in the economic analysis can be self-administered. One-way and probabilistic sensitivity analyses were developed and cost effectiveness acceptability curves generated.RESULTS: In the base-case analysis, DMF was more efficacious than alternatives, in terms of both survival (19.496 vs. 19.297-19.461 discounted LYs, respectively), and QALYs (6.548 vs. 5.172- 6.212 discounted QALYs, respectively). Per-patient lifetime costs with DMF amounted to € 276,500, similarly to the other options. DMF was the drug with the largest effect of disability cost reduction. DMF was dominant vs. IFN beta-1a 44 mcg and cost-effective vs. all other IFNs, GA and teriflunomide, with incremental cost-effectiveness ratio (ICERs) between € 11,272 and € 23,409. All ICER values were lower than the € 50,000 per QALY threshold. One-way sensitivity analysis showed that, for all tested scenarios, ICER of DMF vs. therapeutic alternatives remained favourable (≤ 50.000 €/QALY gained) and the results of probabilistic sensitivity analysis showed that the probability for DMF of being favourable (≤ 50.000 €/QALY gained) was between around 70% and 93%, thus ensuring robustness of the results.CONCLUSIONS: The results of this economic analysis show that, at the current price and the described assumptions, DMF represents a cost-effective option vs. other available first-line treatments indicated in RRMS in the perspective of the Italian NHS.[Article in Italian]

Chronic inflammatory rheumatic diseases (RDs) trigger high costs for healthcare systems and society due to the disability and comorbidity associated with these disease entities. The aim of this study was to analyze patients with RD, assess the use of conventional synthetic and biologic therapies, and estimate the overall cost of treatment in Italy.Administrative healthcare claims from the Piedmont region in Northwest Italy were reviewed to identify patients who received disease-modifying antirheumatic drugs (DMARDs) between 2007 and 2010. Confirmation of RD was based on: (1) diagnosis-specific exemption code; (2) hospitalization or emergency care events characterized by disease-specific ICD9 codes; (3) inclusion in the regional registry of biologic drugs. The follow-up period was 3 years.A total of 9560 subjects, of whom the majority were women (58.1%), were entered into the study; the average age of the study population was 55.3 years. On the index date 12.9% of patients were receiving a biologic DMARD, with adalimumab the most frequently prescribed biologic DMARD (4.7%), followed by etanercept (4.4%). The average total healthcare expenditure was €377.98 per patient per month (patient-month). In the subgroup analysis of healthcare costs according to use of biologics, the total expenditure was €1037.97/€230.86 patient-month for those receiving/not receiving at least one biologic DMARD. In the subgroup analysis of healthcare costs according to type of biologic used, the total expenditure ranged from €657.61 (golimumab) to €1384.15 (rituximab) patient-month.A substantial difference in the total costs according to treatment/no treatment with a biologic and the specific biologic DMARD prescribed was identified. However, this result should be interpreted with caution as a bias in terms of patient selection was most likely present. The results of this study shed some light on RD in an relevant sample of Italian patients. The preliminary conclusions need to be confirmed by further analysis.

Background: The World Health Organization estimated that 90% of the infected people need to be diagnosed and 80% need to be treated to reach the aim of hepatitis C virus (HCV) elimination by 2030. For this reason, all possible strategies to detect and treat HCV-infected people need to be carefully evaluated to implement the best one. Aim: To review and synthesise the economic evaluations of HCV screening programs conducted in the era of direct-acting antiviral agents regimens. Methods: A systematic literature review was conducted until April 2018 to provide information on the costs and effectiveness of HCV screenings in direct-acting antiviral agents era. A critical assessment of the quality of economic evaluations retrieved was conducted. Results: The literature search identified 716 references; 17 of them assessed cost and effectiveness of screening programs and antiviral treatments in different populations: general population (n=7), drug users (n=5), high-risk populations (n=4) and other populations (n=3). The HCV screening and direct-acting antiviral agents treatment appear to be good value for money, both in general and high-risk populations, if a cost per quality adjusted life years of $50000 is set as willingness to pay threshold. Some studies showed the value of including lower stage of fibrosis in the treatment selection criteria. Conclusions: Several HCV screening strategies plus direct-acting antiviral agents treatments resulted cost-effectiveness in different populations. However, there is still need of country and population-specific evaluations within the different HCV screening and treatment strategies available, in order to assess their cost-effectiveness and sustainability and fully support an evidence-informed policy for HCV elimination

Background and aims Rapid virologic response is the best predictor of sustained virologic response with dual therapy in genotype-1 chronic hepatitis C, and its evaluation was proposed to tailor triple therapy in F0–F2 patients. Bio-mathematical modelling of viral dynamics during dual therapy has potentially higher accuracy than rapid virologic in the identification of patients who will eventually achieve sustained response. Study's objective was the cost-effectiveness analysis of a personalized therapy in naive F0–F2 patients with chronic hepatitis C based on a bio-mathematical model (model-guided strategy) rather than on rapid virologic response (guideline-guided strategy). Methods A deterministic bio-mathematical model of the infected cell dynamics was validated in a cohort of 135 patients treated with dual therapy. A decision-analytic economic model was then developed to compare model-guided and guideline-guided strategies in the Italian setting. Results The outcomes of the cost-effectiveness analysis with model-guided and guideline-guided strategy were 19.1–19.4 and 18.9–19.3 quality-adjusted-life-years. Total per-patient lifetime costs were €25,200–€26,000 with model-guided strategy and €28,800–€29,900 with guideline-guided strategy. When comparing model-guided with guideline-guided strategy the former resulted more effective and less costly. Conclusions The adoption of the bio-mathematical predictive criterion has the potential to improve the cost-effectiveness of a personalized therapy for chronic hepatitis C, reserving triple therapy for those patients who really need it.

Introduction: \ud Etelcalcetide is a novel intravenous calcimimetic for the treatment of secondary hyperparathyroidism (SHPT) in haemodialysis patients. The clinical efficacy and safety of etelcalcetide (in addition to phosphate binders and vitamin D and/or analogues [PB/VD]) was evaluated in three phase III studies, including two placebo-controlled trials and a head-to-head study versus the oral calcimimetic cinacalcet.\ud \ud Objective: \ud The objective of this study was to develop a decision-analytic model for economic evaluation of etelcalcetide compared with cinacalcet.\ud \ud Methods: \ud We developed a life-time Markov model including potential treatment effects on mortality, cardiovascular events, fractures, and subjects’ persistence. Long-term efficacy of etelcalcetide was extrapolated from the reduction in parathyroid hormone (PTH) in the phase III trials and the available data from the outcomes study in cinacalcet (EVOLVE trial). Etelcalcetide was compared with cinacalcet, both in addition to PB/VD. We applied unit costs averaged from five European countries and a range of potential etelcalcetide pricing options assuming parity price to weekly use of cinacalcet and varying it by a 15 or 30% increase.\ud \ud Results: \ud Compared with cinacalcet, the incremental cost-effectiveness ratio of etelcalcetide was €1,355 per QALY, €24,521 per QALY, and €47,687 per QALY for the three prices explored. The results were robust across the probabilistic and deterministic sensitivity analyses.\ud \ud Conclusions: \ud Our modelling approach enabled cost-utility assessment of the novel therapy for SHPT based on the observed and extrapolated data. This model can be used for local adaptations in the context of reimbursement assessment.

INTRODUCTION: The EMPA-REG OUTCOME trial demonstrated the efficacy of empagliflozin in the treatment of type 2 diabetes (T2D) with a previous history of cardiovascular (CV) disease. The drug is currently reimbursed for T2D Italian patients, but the reduction of CV mortality and morbidity shown in the trial opens a new treatment perspective in those patients with associated high CV risk.OBJECTIVE: Cost-effectiveness analysis of empagliflozin for the treatment of T2D patients with a previous history of CV disease, from the Italian National Health Service (NHS) perspective.METHODS: The analysis was performed with an individual simulation model, which can predict the time to CV events or death through a set of time-dependent regressions estimated on the patient-level data of the EMPA-REG OUTCOME trial. This design allows the direct simulation of long-term outcomes and costs without the need for surrogate endpoints.The model was adapted to the Italian setting, considering local epidemiological data, baseline quality of life (QoL) utility, background mortality and unit costs from current prices and tariffs. The cost perspective was that of the Italian NHS and the horizon of the simulation was lifetime. Costs and benefits were discounted at a 3.5% rate.RESULTS: Base case results were estimated on a cohort of 5,000 patients, which ensured the convergence of the simulation. Patients treated with empagliflozin in add-on to the standard of care (SoC) lived on the average 13.8 undiscounted years as compared to 11.8 years of patients on SoC alone. The gain in discounted quality-adjusted life years (QALYs) was 1.0, due to improved survival and QoL linked to the reduced incidence of CV events and CV mortality. The incremental cost-effectiveness ratio (ICER) was 4,811 €/QALY, well below the commonly applied threshold of 30,000-50,000 €/QALY.CONCLUSION: Empagliflozin in add-on to the SoC is a highly cost-effective strategy for the treatment of T2D patients with known CV disease in the Italian setting.

IntroductionBevacizumab is a monoclonal antibody, which, in association with combination chemotherapy regimens, has been shown to be active in metastatic colorectal cancer. Other biologic agents active in the same setting are cetuximab and panitumumab, both of which are monoclonal antibodies directed against the antiepidermal growth factor receptor. The objective of this study was to compare treatment costs of first-line regimens for metastatic colorectal cancer in Italy.MethodsA set of first-line regimens was considered, according to the Italian Association of Medical Oncology and the European Society for Medical Oncology guidelines. A targeted review of the literature was undertaken to identify clinical study references for treatment regimens. The total cost of a regimen was calculated in the perspective of the Italian healthcare system summing up drugs, administration, and adverse event costs, based on year 2016 prices and tariffs.ResultsBevacizumab 7.5 mg + capecitabine was the least expensive regimen, with a total cost of €16,754 per patient. When we consider regimens based on FOLFOX, bevacizumab 5 mg + FOLFOX4 was the least expensive (€32,709 per patient), compared to panitumumab + FOLFOX4 (€42,815), cetuximab + FOLFOX4 (€42,725), and cetuximab + FOLFOX (€37,995). If we consider combination regimens based on FOLFIRI, the association of FOLFIRI and bevacizumab was less expensive than regimens that included cetuximab (€28,389 for bevacizumab 5 mg + FOLFIRI and €35,310 for cetuximab + FOLFIRI).ConclusionsFrom the perspective of the Italian health care system, bevacizumab appears to be a convenient option among the first-line regimens for metastatic colorectal cancer. Further study, based on real-world evidence, would be necessary to confirm this result.

OBJECTIVES Switching to a different mechanism of action in rheumatoid arthritis (RA) patients after a first anti-TNF-α has proved to be effective. The objective of this study was a health economic assessment in Italy. METHODS The study was conducted using a pharmacoeconomic model with a 3-year time horizon. Effectiveness was measured as days gained in low disease activity (LDA; DAS28-ESR

Background and objective Treatment options for chronic hepatitis B (CHB) are the direct inhibition of viral replication by continuous administration of nucleoside analogues (NUCs) or a finite 48-week course of peg-interferon (PEG). PEG can induce the off-therapy immune control of CHB leading to HBsAg loss/anti-HBs seroconversion, but with a low success rate. On the other hand life-long treatment with NUCs is expensive. Currently in Italy, around 67% of naive patients receive treatment with NUCs. However, exploiting the early identification of PEG-non-responders by combined HBV-DNA and HBsAg quantification at week 12 (stopping-rule) is a new sequential therapeutic strategy that may benefit both patients and third payers. We measured the impact on the Italian National Health Service (NHS) budget of the strategy PEG-week-12-stopping-rule in the treatment of HBeAg-negative CHB.

BACKGROUND AND OBJECTIVE: Pharmacological approaches available in chronic hepatitis B (CHB) are based on 48-weeks finite course of peg-interferon (PEG-IFN) or continuous administration of nucleoside analogues. Recent studies gave way to early identification of non-responders to peg-interferon with a stopping rule based on virologic/serologic markers at week 12. A pharmacoeconomic simulation model was developed to support the economic evaluation of HBeAg-negative CHB treatment strategies, which either involve first line peg-interferon with stopping rule and switch to current most effective analogue entecavir or tenofovir, or nucleosides analogues in first line treatment. This model showed a good cost-effectiveness profile of the first line treatment with peg-interferon. Aim of the present study was the estimation of the impact of a wide adoption of a first line with PEG-IFN and the stopping rule on total overall cost related to CHB over the lifetime of patients in Italy.METHODS: The Markov model was developed to perform a lifetime simulation of the disease progression considering the following health-related states: active CHB, virologic response, HBsAg clearance, compensated cirrhosis with active CHB, compensated cirrhosis with virologic response, decompensated cirrhosis, hepatocellular carcinoma, liver transplant, post-liver transplant and death. The outcomes provided by the model were average survival, quality-adjusted life years (QALY) and costs, calculated from the Italian National Health Service (SSN) perspective. A “current” mix of treatments, where 80% patients received ETV or TDF in first-line, was compared with an “hypothetical” mix defined by a 100% adoption of a PEG-IFN first-line with the stopping rule, to estimate the impact on total lifetime CHB-related costs for a cohort of 100 HBeAg-negative CHB patients in Italy.RESULTS: Results obtained from the evaluation of overall total treatment cost over patients’ lifetime appeared to confirm the cost-effectiveness of peg-interferon previously assessed. Lifetime overall total cost resulted significantly lower with the “hypothetical” treatment mix as compared to the “current” mix.. In fact, estimated lifetime overall total costs for the former and latter scenario were equal to €7,239,050 and €9,060,150 respectively, thus generating a saving of approximately 20% associated to CHB treatment with first-line peg-interferon.CONCLUSION: Based on the results obtained from the economic evaluation of the CHB treatment strategies, first-line peg-interferon associated with the stopping rule and switch to nucleoside analogues consistently represents a convenient strategy on both the clinical and economic perspective.

Rheumatoid arthritis (RA) is an autoimmune chronic disease which is associated with an increasing disability in patients and high socioeconomic burden. Given the large number of economic evaluations considered by national health technology assessments (HTAs), this review attempts to clarify whether results from biologic disease-modifying antirheumatic drugs (DMARDs) economic evaluations form the basis of official recommendation by national HTA agencies in Australia, Canada, Scotland and England. The results show that evidence of cost-effectiveness was not equally perceived by decision makers and did not have equal weightage in defining the official listing of biologic DMARDs for the treatment of RA. As it has been demonstrated in previous studies, major barriers exist for the integration of cost-effectiveness and cost-utility results with national HTA activity. In fact, as shown in this review, even when such analysis are available, cost-minimization and comparative effectiveness studies seemed to be preferred by some HTA agencies as tools to inform allocation of healthcare resources.

Background Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) is the most frequent and difficult-to-treat viral hepatitis worldwide. HBV DNA and hepatitis B surface antigen (HBsAg) serum levels, which help the early identification of non-responders to pegylated interferon (PEG-IFN), prompt more flexible individualized therapeutic strategies exploiting the benefits of both PEG-IFN and nucleoside/nucleotide analogues (NAs). We assessed the cost-effectiveness of week-12 HBV DNA/ HBsAg stopping rule for early interruption and switch to currently most effective NA treatments (entecavir [ETV] or tenofovir disoproxil fumarate [TDF]). Methods A decision-analytic Markov model was developed in the following health-related states: CHB, compensated cirrhosis (CC) and decompensated cirrhosis, hepatocellular carcinoma, liver transplant, post-liver transplant, death, virological response, relapse and HBsAg clearance. Simulated strategies included: ETV/TDF in CHB; ETV/TDF delayed until CC; first-line PEG-IFN followed by switch to ETV/TDF for either patients meeting the week-12 stopping rule or week-48 null-responders/relapsers; and first-line PEG-IFN followed by switch to ETV/TDF delayed until CC. ETV and TDF were considered alternatively for a total of eight strategies. A lifetime simulation horizon was applied. Results Early treatment strategies using NAs with or without first-line PEG-IFN provided the highest results (approximately 22 life-years and 15 quality-adjusted life years [QALYs]). Delayed treatments until cirrhosis development resulted in poorer outcomes. The average per-patient lifetime costs ranged from €33,500 (TDF in CC) to €68,900 (TDF in CHB). Costs using ETV were 20–50% higher. First-line PEG-IFN strategies ranged from dominant (that is, more effective and less costly) to highly cost-effective, although differences in QALYs were always very narrow. Conclusions The cost-effectiveness of antiviral therapy of HBeAg-negative CHB could be improved significantly using first-line PEG-IFN followed by a switch to NAs in either patients meeting the week-12 HBV DNA/HBsAg stopping rule or week-48 non-responders/relapsers.

The objective of this study was to assess the cost-effectiveness of pharmacokinetic-driven prophylaxis in severe haemophilia A patients. A microsimulation model was developed to evaluate the cost-effectiveness of pharmacokinetic-driven prophylaxis vs. standard prophylaxis and estimate cost, annual joint bleed rate (AJBR), and incremental cost-effectiveness ratio over a 1-year time horizon for a hypothetical population of 10 000 severe haemophilia A patients. A dose of 30 IU/kg per 48 h was assumed for standard prophylaxis. Pharmacokinetic prophylaxis was individually adjusted to maintain trough levels at least 1 and 5 IU/dl or less. AJBR was estimated on the relationship between factor VIII (FVIII) levels and bleeding rate reported in the literature. Sensitivity analyses were performed to assess the stability of the model and the reliability of results. The FVIII dose was reduced in the 27.8% of patients with a trough level more than 5 IU/dl on standard prophylaxis, with a negligible impact on AJBR (+0.1 bleed/year). The FVIII dose was increased in the 10.6% of patients with trough levels less than 1 IU/dl on standard prophylaxis, with a significant reduction of AJBR (-1.9 bleeds/year). On average, overall, pharmacokinetic-driven prophylaxis was shown to decrease the AJBR from 1.012 to 0.845 with a slight reduction of the infusion dose of 0.36 IU/kg, with total saving of 5 197OV0556; per patient-year. Pharmacokinetic-driven prophylaxis was preferable (i.e. more effective and less costly) compared with standard prophylaxis, with savings of 31 205OV0556; per bleed avoided. Pharmacokinetic-driven prophylaxis, accounting for patients' individual pharmacokinetic variability, appears to be a promising strategy to improve outcomes with efficient use of available resources in severe haemophilia A patients.

Background: Asthma is a common disease of the airways with a significant burden for the society and for patients’ quality of life. The Social Impact of Respiratory Integrated Outcomes (SIRIO) study estimated a mean cost of 1,177.40 € per patient/year in Italy, in 2007. The aim of the present study was to update the cost of persistent asthma patients in Italy. Methods: An observational, retrospective, bottom-up analysis was carried out starting from the data base operating in the Lung Unit of the Specialist Medical Centre (CEMS), Verona (Italy), over the period June 2013-December 2015. Patients’ data were recorded over the 12 ± 2 months before the enrollment and during 12 ± 2 months of follow-up. The prospective was the Italian National Health Service and the broad Italian society. Clinical data were measured in terms of forced expiratory volume in 1 s (FEV1%) and number of relapses. Healthcare resources (namely; number of hospitalizations and/or ER admissions; number of visits; drug use and duration, and indirect costs) were recorded. Results: The cohort consisted of 817 patients with persistent asthma of different severity. They had a 42.96% male prevalence; a mean (±SE) age of 49.06 (±0.64) years; a mean 87.47% (±0.81) FEV1% pred. in baseline, and 69.16% of subjects had comorbidities. The mean (±SE) number of relapses was 0.91 (±0.09) per patient/year before the enrolment. After 12 months, FEV1% significantly improved by +6.31% (±0.45) from the corresponding baseline value (p < 0.001). The number of relapses decreased of −0.46 (±0.09) (p < 0.001). The estimated total annual cost per asthmatic patient was 1,183.14 € (±65.79 €) during the 12 months before the enrolment, and 1,290.89 € (±68.74 €) throughout the follow-up. The increase was mostly due to the significantly increased duration of therapeutic strategies. The costs of hospitalization, general practitioner and rescue medications were significantly decreased. Conclusions: The periodic update of cost analysis is a key to monitor the trend of main asthma outcomes and related expenditure over time. It allows to plan the most convenient actions in terms of prevention strategies and effective interventions, with the aim of optimizing the healthcare resources consumption and maximizing the impact on clinical outcomes and patients’ quality of life. The role of an appropriate pharmacological strategy still proves crucial in minimizing asthma morbidity and the corresponding socio-economic impact.

BACKGROUND: Each drug therapy with an anticoagulant effect may require, in emergency conditions, a rapid and specific strategy for a prompt restoration of coagulation. Dabigatran is the first-in-class of the so-called new oral anticoagulants (NAO), that have been made available in recent years in addition to traditionally-used vitamin K antagonists (VKA). Idarucizumab is a monoclonal antibody that binds to dabigatran, neutralizing its anticoagulant effect.OBJECTIVE: To assess the economic effect of idarucizumab in patients treated with dabigatran when the rapid reversal of its anticoagulant effect is required.METHODS: The analysis was carried over through the development of a budget impact model specifically adapted to the context of Italian care. The analysis was conducted along a time horizon of five years. The target population was defined by those patients on dabigatran treatment presenting uncontrolled and life-threatening bleedings (gastro-intestinal, intracranial or other) or requiring emergency surgery or urgent procedures. The estimation of healthcare resources (i.e. diagnostic procedures, medications, and other in-hospital services) needed for the management of uncontrolled bleeding and emergency surgery in patients treated with dabigatran was obtained from a panel of five Italian Clinical Experts. Unit costs were derived from current prices and tariffs.RESULTS: The total cost of management with the current therapeutic modalities ranged from € 16.5 million in year 1 to € 20.1 million in year 5. In the scenario with idarucizumab the total cost ranged from € 15.4 million in year 1 to € 18.7 million in year 5. The adoption of idarucizumab resulted in a cumulative 5-year savings of 6.5 million euro corresponding to 7.1% of the total expense.CONCLUSION: Idarucizumab for the management of patients treated with dabigatran in emergency / urgent situations has the potential for substantial savings, compared to treatments currently available. This preliminary assessment will require further confirmatory evidence when the product will become available in Italian healthcare setting.[Article in Italian]

Background and Objective:Background and Objective: A probabilistic patient-level Markov model was previously developed to simulate lifetime clinical and economic outcomes of cinacalcet treatment in secondary hyperparathyroidism (SHPT) patients using local data from Italy. The present study extends the application of the model to four other European countries - Spain, Portugal, Switzerland and the Czech Republic - in order to assess the consistency of results. Abstract: Methods:Methods: Cinacalcet influences the levels of parathyroid hormone, serum calcium and phosphorous. Our simulation was based on data from the OPTIMA (Open-Label, Randomized Study Using Cinacalcet to Improve Achievement of KDOQI Targets in Patients with End-Stage Renal Disease) randomized controlled trial and from published correlations between bone-metabolism parameters, mortality and morbidity (cardiovascular &lsqb;CV&rsqb; events, fractures and parathyroidectomy). Local epidemiological and cost data for dialysis, drugs and event management were incorporated into the model. The simulation horizon was patient lifetime; standard treatment for SHPT (vitamin D sterols and phosphate binders) and cinacalcet plus standard treatment were compared. Effectiveness was measured in terms of life expectancy (LE) and quality-adjusted life expectancy (QALE). Health utility indexes derived from published literature took into account dialysis, CV events and fractures. Abstract: Results:Results: The simulated mean LE extension in patients receiving cinacalcet was 1.20 life-years (LY) in Italy, 1.10 LY in Spain, 1.18 LY in Portugal, 1.10 LY in the Czech Republic and 1.40 LY in Switzerland. QALE increase was 0.89, 0.82, 0.89, 0.80 and 1.01 QALY in the same countries, respectively. The incremental cost-effectiveness ratio (ICER) result was &U20AC;23 500/LY and &U20AC;31 600/QALY in Italy, &U20AC;21 800/LY and &U20AC;29 300/QALY in Spain, &U20AC;23 700/LY and &U20AC;31 200/QALY in Portugal, &U20AC;29 700/LY and &U20AC;40 800/QALY in the Czech Republic and &U20AC;24 700/LY and &U20AC;34 200/QALY in Switzerland. Including dialysis costs as a part of the total costing doubled the ICER, from a minimum of &U20AC;42 800/LY in Spain to a maximum of &U20AC;82 800/LY in Switzerland and in the range from &U20AC;57 500/QALY (Spain) to &U20AC;114 700/QALY (Switzerland). Abstract: Conclusion:Conclusion: Taking into consideration the limited clinical, epidemiological and health economics data available, cinacalcet treatment showed a relatively good cost-effectiveness profile in all the countries analysed, despite the differences in their healthcare systems and economic wealth.

Background: a secondary pre-specified analysis of the UPLIFT cohort demonstrated that the inclusion of tiotropium bromide in the routine care of GOLD stage II (moderate) chronic obstructive pulmonary disease (COPD) patients is associated with stronger improvements of survival, quality of life, and exacerbation rate than those shown in the total cohort; in this subgroup, tiotropium furthermore induces a significant reduction in the rate of FEV1 decline.Objective: to adapt the Spiriva® model, originally built to evaluate cost-effectiveness of tiotropium inclusion in the general COPD population, to GOLD II patients.Methods: the Spiriva® model is a probabilistic Markov patient-level simulation developed over a lifetime horizon to compare outcomes associated with the inclusion of tiotropium in routine care (RC) for COPD treatment with those obtained with RC alone. Patients are characterised by gender, age, height, smoking status and FEV1. Model structure and sources have been maintained unvaried, except for demographic characteristics, specific for GOLD II patients, as extrapolated from an Italian observational study, and tiotropium efficacy, based on the secondary analysis of GOLD II UPLIFT patients. As in the original model, only direct health care costs are considered.Results: patients treated with tiotropium on average (95% CI) gain 0.70 (0.00/7.23) LYs or 0.77 (0.02/4.67) QALYs compared to RC. The incremental lifetime cost is € 3,520 (-6,391/26,686), meaning that the incremental cost required to gain a QALY (incremental cost-effectiveness ratio – ICER) is equal to € 4,548. Sensitivity analysis shows that tiotropium has a 50% probability of being cost-effective for a willingness-to-pay (WTP) around 4,600 €/QALY; 100% probability is achieved with a WTP of € 9,300.Conclusions: the adoption of a strategy based on the inclusion of tiotropium from the early COPD stages represents good value for money in Italy, as the ICER estimated for GOLD II patients is well below conventional WTP thresholds, and lower than that calculated for the entire UPLIFT cohort.

Introduction and objective: ziconotide is the first-in-class drug of selective N-type voltage-sensitive calcium-channel blockers used to control severe chronic pain. The present study is developed in order to analyze clinical and economical outcomes of spinal neuromodulation with ziconotide continuous infusion in cancer pain in a real clinical practice.Methods: costs and effects of ziconotide are compared with those of traditional neuromodulation with morphine and adjuvant drugs, administered by intrathecal infusion.Effectiveness and resources consumption data were retrospectively collected in 22 patients with severe complex cancer pain followed by one Italian centre from the day of port implantation to drop-out , due to death or consent withdrawal. 11 patients received morphine regimens and the other 11 were treated with ziconotide. The evaluation of the number of days with controlled pain (i.e., with an at least 30% reduction on the Numeric Rating Scale-Pain Intensity, NRSPI) is the primary outcome of the analysis. The evaluated consumed health resources include drugs, visits, port maintenance, and pump recharge and amortization. Current Italian prices, real practice acquisition and remuneration costs borne by the third payer are applied.Results: patients receiving ziconotide lived significantly more days with controlled pain (78% vs 40%; p < 0.05). Average weekly cost is about 232 € for ziconotide and 120 € for morphine; the main driver being the pharmaceutical cost (respectively 81% and 65% of the total). Higher ziconotide acquisition costs are partially offset by minor expenses for adjuvant therapies, as ziconotide-treated patients on average receive a lower number of drugs than those receiving a traditional regimen. The incremental cost for one further day with controlled pain resulted of 42,30 €.Conclusions: ziconotide permits effective treatment of extremely difficult-to-manage pain, with a mild increment of cost, as compared to intrathecal morphine-based therapy.

Background: Imbalanced levels of parathyroid hormone (PTH), serum calcium (Ca) and phosphorous (P) are associated with an increased risk of cardiovascular (CV) death and fracture in dialysis patients with secondary hyperparathyroidism (SHPT). The calcimimetic agent cinacalcet can attenuate the mineral and hormonal imbalances characteristic of SHPT and may improve outcomes in such patients. Here we describe a cost-utility analysis of cinacalcet for SHPT in dialysis patients in Italy. Methods: We developed a probabilistic Markov model to simulate the effect of cinacalcet on Ca, P and PTH levels in dialysis patients with SHPT, based on data from a European, multicentre, open-label study. The model then correlated these levels with mortality and morbidity (CV events, fractures and parathyroidectomies) using data from the literature, and incorporated Italian data for dialysis, drugs and management of events according to the national cost structure. The simulation horizon was patient lifetime; simulated treatment alternatives were standard treatment (mainly vitamin D sterols and phosphate binders) and cinacalcet + standard treatment. A 3.5% discount rate was applied to life expectancy (LE), quality-adjusted life-expectancy (QALE), costs and times below the upper ranges (time in range &lsqb;TiR&rsqb;) recommended by the National Kidney Foundation - Kidney Disease Outcomes Quality initiative for PTH, Ca, P and Ca × P. Utilities were derived from the published literature and took into account dialysis and the impairment of quality of life due to the occurrence of CV events and fractures. Costs were evaluated in year 2009 values from the perspective of the Italian National Healthcare System. Results: Baseline results were calculated with 10 000 iterations. Compared with standard treatment alone, addition of cinacalcet was associated with a mean (SD) increase in TiR of 5.26 (6.59), 3.63 (6.87), 1.70 (6.66) and 2.68 (5.55) discounted patient-years for PTH, Ca and P, respectively, and combined PTH, Ca, P and Ca × P. Cinacalcet increased LE by 1.20 (3.75) life-years (LYs) and QALE by 0.89 (2.59) QALYs. When including the cost for dialysis, the incremental cost-effectiveness ratio (ICER) was &U20AC;50 012 per LY and &U20AC;67 361 per QALY, while, if dialysis costs were not included, the ICER was &U20AC;23 473 per LY and &U20AC;31 616 per QALY. Conclusions: The results suggest that cinacalcet treatment could be considered cost effective for treatment of SHPT in the Italian healthcare setting, but further investigations are needed to confirm these findings.

The management of the large patient population in Italy receiving long-term oral anticoagulation therapy (OAT) poses organizational challenges that are traditionally approached with a centralized procedure, relying on hospital-based clinics and/or GPs. However, the availability of near-patient testing devices for the monitoring of OAT effectiveness (international normalized ratio measurement) allows for alternative or complementary management models, in which adequately trained patients perform the test themselves and possibly make decisions about dosing adjustments (patient self-monitoring). Patient self-monitoring has been proven to be effective and safe, and is economically attractive. However, in order to assess its potential economic impact in Italy, there is a need for data on current treatment patterns and relative costs, which are currently not available. To establish prevalent management patterns and costs incurred by Italian OAT patients. An ad hoc questionnaire was developed and administered to OAT patients with the support of the main Italian OAT patients association. Returned questionnaires were checked for consistency and valid data were summarized. Resources used were costed according to published prices. A total of 4722 valid questionnaires were returned from all over Italy. The prevalent OAT management model in this sample relied on hospital-based anticoagulation clinics. Significant earning losses, transportation costs and other out-of-pocket expenses were incurred by patients, with an estimated mean overall monthly cost of approximately €30 (year 2008 value). There was a wide distribution of costs in this population, depending mainly on monitoring frequency, home-to-clinic distance and employment status. This study contributes to clarifying the organizational models of the Italian OAT population and delivers data on treatment patterns and costs that may be used when planning and evaluating alternative management options.

To evaluate the cost effectiveness and cost utility of the use of valsartan in addition to standard therapy for the treatment of patients with chronic heart failure with low left ventricular ejection fraction (LVEF). The study was conducted by means of a cohort simulation based on a probabilistic Markov model and projecting the 23-month follow-up results of the Val-HeFT (Valsartan Heart Failure Trial) study over a 10-year time horizon. The model included four states (New York Heart Association [NYHA] classes II, III, IV, and death), and had a cycle duration of 1 month. Probabilistic simulations were performed using the WinBUGS software for Bayesian analysis. The distribution of patient parameters (sex, age, use of beta-adrenoceptor antagonists, and ACE inhibitors) in the simulated population were derived from the Italian heart failure patient population. Individual mortality data were derived from general mortality data by multiplying by a NYHA state-specific relative risk, while the probability of changing NYHA class was taken from the Val-HeFT data. Costs (2007 values) were calculated from the perspective of the Italian Health Service (IHS) and included costs for drugs and heart failure hospitalizations. Quality-of-life (QOL) weights were obtained by using published health-related QOL data for heart failure patients. A 3.5% annual discount rate was applied. Probabilistic sensitivity analysis was performed on each parameter using original-source 95% confidence interval (CI) values, or a +/-10% range when 95% CI values were unavailable. For the 10-year time horizon, patients were estimated to live for an average of 2.3 years or 1.7 quality-adjusted life-years (QALYs), with slight increases in the valsartan group. In this group, hospitalizations for worsening heart failure were predicted to be significantly reduced and overall treatment costs per patient to decrease by about and U20AC;550. In subgroup analyses, valsartan lost dominance in patients in NYHA II, and in those receiving beta-adrenoceptor antagonists or ACE inhibitors; the mean incremental cost-utility ratio for these groups was 21 240, 129 200, and 36 500 and U20AC;/QALY, respectively. Valsartan in addition to standard therapy is predicted to dominate standard therapy alone in Italian patients with mild to severe heart failure and low LVEF. There are relevant differences among various patient subgroups, and valsartan is expected to be good value for money particularly in the treatment of the most severe and less intensively treated (no ACE inhibitors, no beta-adrenoceptor antagonist) heart failure patients.

Introduction: the supplementation of alanyl-glutamine dipeptide in critically ill patients necessitating total parenteral nutrition (TPN) improves clinical outcomes, reducing mortality, infection rate, and shortening ICU hospital lengths of stay (LOS), as compared to standard TPN regimens. Here we present a pharmacoeconomic evaluation of alanyl-glutamine dipeptide in critically ill patients admitted to Italian Intensive Care Units (ICUs). Methods: a Discrete Event Simulation model that incorporates outcomes rates from 200 Italian ICUs for over 60,000 patients, alanyl-glutamine dipeptide efficacy data synthesized by means of a Bayesian Random-Effects meta-analysis, and national cost data has been developed to evaluated the alternatives from the point of view of the hospital. Simulated clinical outcomes are death and infection rates in ICU, death rate in general ward, and hospital LOSs. One-way and probabilistic sensitivity analyses are performed by varying all uncertain parameter values in a plausible range. Results: alanyl-glutamine dipeptide results more effective and less costly than standard TPN: reduced mortality rate (23.55% ± 15.2% vs 34.50% ± 2.06%), infection rate (15.91% ± 3.95% vs 18.97% ± 3.94%), and hospital LOS (25.47 ± 0.26 vs 26.00 ± 0.27 days) come at a lower total cost per patient (23,922 ± 3,249 vs 24,145 ± 3,361 Euro). Treatment cost is completely offset by savings on ICU and antibiotic costs. The cost/effectiveness acceptability curve indicates an estimated 78% probability of alanyl-glutamine dipeptide resulting dominant and a 90% probability of resulting cost/effective for a willingness to pay up to 1,500 Euro for one patient death avoided. Conclusions: alanyl-glutamine dipeptide is expected to improve clinical outcomes and to do so with a concurrent saving for the hospital.

Background: influenza infection is an important cause of morbidity and mortality in the elderly population, especially in the presence of underlying disease. Vaccination has proven effective in the reduction of influenza-like illness (ILI) cases and influenza-related hospitalizations, drug consumption, primary care consultations and death. The aim of this study is to assess the economic impact in Italy of different prophylactic strategies (vaccination with a standard vaccine, with the innovative MF59® adjuvated vaccine and no vaccination) comparing their costs and outcomes in the elderly population. Methods: a pharmacoeconomic simulation model to estimate costs and consequences of influenza with the three intervention strategies has been developed. Health economics and demographic data are taken from specific Italian sources, and vaccine effectiveness data are taken from published literature. Direct sanitary costs are considered according to current prices and tariffes. Results: it was estimated that 9,800,000 of the about 12,000,000 people with at least 65 years currently resident in Italy can be considered at high risk for influenza complications because of underlying chronic diseases. Absence of vaccination could lead to more than 2 millions of ILI cases, and 30,000 related deaths. The reduction of cases attainable with the implementation of a vaccination program would lead to an estimated 1.5 million cases with a standard vaccine, and to 1.3 million with a strategy based on the MF59® adjuvated vaccine. The standard vaccination strategy could produce a moderate total cost increase of about € 45,000,000 (+4.3%), whereas the use of the adjuvated vaccine would lead to an estimated saving of about € 80,000,000 (-7.9%), both compared to the null option. Cost savings are mainly related to hospital admissions avoided with the use of vaccines. Incremental cost-effectiveness ratio (ICER) of the standard vaccine versus no vaccination strategy is of € 85.68 for each ILI episode avoided, and of € 4,411.42 for death avoided. The strategy based on the MF59® adjuvated vaccine dominates the other two options. Conclusions: vaccination with the MF59® adjuvated vaccine (Fluad®) results more effective and cost saving when compared with the standard vaccination or the no vaccination, thus representing the strategy of choice for the elderly population. Moreover, the standard vaccine proved to be largely cost effective with respect to the null option.

Objective: a Budget Impact analysis was performed to evaluate cost implications for the Italian National Health Service (NHS) of the introduction of rituximab (RTX) in the treatment of rheumatoid arthritis (RA). Methods: RA patients eligible to treatment with a second-line biologic DMARD (Disease Modifying Antirheumatic Drugs) were identified and quantified and available strategies for their management were explored. Costs associated with the different alternatives were estimated, and the impact on the NHS budget was estimated using a cohort simulation based on a Markov chain with a time horizon of 5 years and 1-year cycles. Seven alternative strategies were analyzed, each of them starting after the failure of a first anti-TNFα: 1) the use of a second and a third anti-TNFα; 2) the use of a second anti-TNFα followed by RTX; 3) the use of a second anti-TNFα followed by abatacept (ABAT); 4) the use of RTX as a second biological line, followed by an anti-TNFα; 5) the use of ABAT as a second biological line, followed by an anti-TNFα; 6) the use of RTX as a second biological line, followed by ABAT; 7) the use of ABAT as a second biological line, followed by RTX. Only direct medical costs were considered: drug acquisition, administration, incidental premedication and monitoring exams. Results: Italian patients eligible to second biological line therapies (RA patients refractory or intolerant to at least one anti-TNFα therapy) were estimated in about 650 per year. The adoption of RTX as a second line therapy produced a substantial saving in total costs (-33% at the fifth year) with respect to the strategy with RTX as third line and the one with only anti-TNFα (the last two resulting substantially cost-equivalent). The number of patients in active treatment (biologic DMARD) per unit cost resulted of about 8.1 patient-years/100,000 € with the strategy based only on anti-TNFα and increased of 10% with RTX as a third line. The strategy of RTX as a second line provided a further 41% increase (with respect to RTX as a third line). Conclusions: the introduction of RTX in the treatment of Italian RA patients represents a valuable new therapeutic option for this population especially if anticipated after a first anti-TNFα failure; it can also induce a reduction in health resources consumption for the NHS.

Objective: to estimate the impact of lapatinib utilization within the Italian National Health Service (NHS) resources consumption. Lapatinib is an oral inhibitor of kinase protein, approved as dual therapy with capecitabine for the treatment of metastatic breast cancer patients with HER2 overexpression who experience disease progression despite trastuzumab treatment. Methods: the analysis is based on a model, which structure can be summarized as follows: a) national cancer registries-based estimate of the yearly number of HER2+ breast cancer patients who develop metastatic disease in Italy; b) literature-based identification of the rate of patients eligible to receive lapatinib; c) identification of the current therapeutic strategy-mix; d) costing of the alternatives, and e) calculation of budget impact. Direct NHS costs (drug acquisition and administration, and monitoring for 8 cycles of 21 days) are estimated based on current Italian prices and tariffs. Results: the annual number of patients eligible for lapatinib-based therapy can vary from 1,676 to 2,172, according to the expected extent of the trastuzumab use as adjuvant therapy. The current strategy-mix beyond progression is based on drugs used in the clinical practice, with a portion of patients continuing trastuzumab. Pharmaceutical cost of lapatinib results higher than the average cost of the current pattern of treatments. This cost increase would be partially offset by the reduction of laboratory tests and hospital personnel work for the oral administration of lapatinib, as compared to intravenous strategies. Furthermore, a risk sharing agreement has been adopted by NHS and manufacturer, according to which the NHS pays only for responding patients. As a consequence, lapatinib-based therapy would increase yearly NHS expenditure by about 3.8-4.9 millions of euro. Conclusions: lapatinib is the only treatment option specifically indicated for the management of HER2+, metastatic breast cancer in patients who received prior treatments including trastuzumab and is estimated to induce a low budget impact for the Italian NHS.

To investigate the pharmacoeconomic performance of treatment with solifenacin, a new antimuscarinic with selectivity for the bladder, when compared to tolterodine and placebo, in Italian patients with overactive bladder (OAB).The evaluation was performed using a Markov model. The time horizon of the simulation was 52 weeks, with 1-week cycles. The model simulated outcomes and costs of the treatment with solifenacin (5 mg/day), tolterodine ER (4 mg/day) and no treatment in a cohort representative of the Italian population with OAB. The analysis was conducted mainly from the perspective of the patient, since drugs for the treatment of OAB are not included in the Italian reimbursement list. A supplementary scenario explored the consequences of a hypothetical reimbursement decision by the Italian Health Service to reimburse half of the current retail price in incontinent and responding OAB patients only.Both treatments produced a reduction in symptoms and improvement in patients' quality of life, with an cost increase of about euro 540-640/patient/year with solifenacin and euro 680-780/patient/year with tolterodine. In a cost/utility analysis, solifenacin dominated tolterodine as it resulted in both more effective and less costly treatment; the cost/utility ratio with respect to no treatment was in the range euro 7,600-18,600/Quality-adjusted life year. The overall expenditure of the hypothesised reimbursement decision was estimated to be about 23 million euros, with a cost/utility ratio of about euro 600-2,400/Quality-adjusted life year, indicating an efficient allocation of health resources.While both tolterodine and solifenacin appear to be cost/effective in Italy, the latter has proven to be superior.

Objective: to evaluate pharmacoeconomic implications of the use of valsartan, an angiotensin II antagonist in addition to standard therapy for the treatment of chronic congestive heart failure (CHF). Methods: the study was conducted performing cost-utility and budget impact (B.I.) analyses by means of a cohort simulation based on a probabilistic Markov model and projecting 23-months follow-up results in the Val-HeFT trial study over a 10-years time horizon. The model included four states (class NYHA I, II and III and death), and had a cycle of 1 year. Two probabilistic simulations (varying first patients parameters and after model parameters) were performed using WinBUGS, a software for bayesian analysis. The distributions of patients parameters (sex, age, use of ACE inhibitors) corresponding to Val-HeFT inclusion criteria in the simulated population were derived from the Italian CHF patients population. Individual mortality was derived from general mortality by adjusting with a NYHA state-specific HR, and the probability of changing NYHA class from Val-HeFT. Costs were calculated in the perspective of the Italian NHS and account for drugs and CHF hospitalizations. Quality of life weights were obtained by elaborating published HRQoL data of CHF patients. A 3.5% annual discount rate was applied; probabilistic sensitivity analysis was performed on each parameter using original-source 95% CI, or a ±10% range where it was unavailable. Results: in the 10 years horizon, patients were estimated to live an average of 4.4 years or 3.2 QALYs, with slight increases in the valsartan group. In this group, hospitalizations are predicted to be sensitively reduced and overall costs decreased by about 500 €/pz. In subgroup analysis, valsartan loses dominance in NYHAII and ACE-using patients, for which ICURs are 17,330 and 27,000 €/QALY, respectively. B.I. analysis predicts a saving of about 172 millions €. Conclusions: valsartan in addition to standard therapy is predicted to be a cost/effective strategy for Italian patients with mild-to-severe CHF and cost-saving from the perspective of the NHS.

The search for a more specific and complete blockade of the hypertensive effects of angiotensin and of better tolerability than ACE-inhibitors has led to the development of angiotensin II receptor blockers (ARBs), which were introduced about 10 years ago. During this period they have been evaluated in several large studies in terms of efficacy and safety in reducing blood pressure, as well as for cardiovascular and renal protection. In patients with heart failure, valsartan, candesartan and, partially, losartan have been shown to be associated with positive outcomes both as monotherapy, when ACE-inhibitors are contraindicated or not tolerated, and in combination with ACE-inhibitors standard therapy. Among ARBs, valsartan is the only that is also approved for treatment of patients with both heart failure and recent myocardial infarction. In light of the high costs related to cardiovascular disorders, agents that reduce cardiovascular risk, like ARBs, represent a potential long-term health cost saving strategy, if used according to guidelines in approved indications. Valsartan has a daily cost which is lower than the mean cost of the class. Furthermore, this drug shows one of the lowest costs for patient brought to blood pressure goals in its class. In this paper, economic evaluations conducted on the results of large trials were reviewed. Their results add economic rationale to the therapeutic algorithms recommended by clinical guidelines on heart failure management; using valsartan, or other evaluated ARBs, in heart failure patients who are intolerant or contraindicated to ACE-inhibitors therapy, is expected to be highly cost/effective. In combination with ACE-inhibitors in those patients not on beta-blocker therapy, its cost/effectiveness is somewhat worse, but still acceptable, with an estimated cost of 15,000 USDs for life year saved. In summary, when used for approved indications, valsartan offers attractive economic features for the healthcare provider and has a positive impact on the cardiovascular morbidity and health-related quality of life of these patient populations.

The overactive bladder (OAB) syndrome can be treated with behavioural, surgical and/or pharmaceutical interventions, mainly represented by antimuscarinic drugs. Solifenacin is a new antimuscarinic with selectivity for the bladder and it demonstrated good effectiveness, safety and tolerability. Scope of the present study is to investigate the pharmacoeconomic performance of the treatment with solifenacin, when compared to tolterodine and placebo, in Italian patients with OAB. The economic evaluation is performed with a simulation model, based on a Markov chain. The time horizon of the simulation is 52 weeks, with a 1-week cycle. The model simulates the outcomes and costs of the treatment with solifenacin (5 mg/die), tolterodine ER (4 mg/die) and no treatment in a cohort representative of the Italian population with OAB (estimated in about 1,400 thousands patients). The cost analysis is conducted mainly in the perspective of the patient, since drugs for the treatment of OAB are currently not included in the Italian reimbursement list. The results show that both treatments produce significative improvements in symptoms and quality of life, with an increase in costs of about 540-640 Euro/year with solifenacin and of 680-780 Euro/year with tolterodine. In the cost-utility analysis, solifenacin dominates tolterodine since it results more effective and less costly, and its cost cost-utility ratio with respect to no treatment is in the range 7,600-18,600 Euro/QALY. In the subgroup of patients incontinent at baseline and who best respond to the therapy (responders), the increase in costs with solifenacin results of about 100-400 Euro/year and the cost-utility ratio is 600-4,200 Euro/QALY. A supplementary scenario has been elaborated to explore the consequences of a hypothetical reimbursement decision by the Italian NHS. In this scenario, the NHS cost perspective is considered and the antimuscarinic drugs are assumed to be reimbursed at a half of the current retail price only to incontinent and responder OAB patients. The overall expenditure of such a decision, which yields clear health outcomes, is estimated in about 23 millions Euro, with a cost-utility ratio of about 600-2,400 Euro/year, suggesting an efficient allocation of sanitary resources.

Modeling by mathematical equations the dynamics of hepatitis C virus (HCV) infection has been helpful to uncover the mechanisms of viral persistence and to study the mode of action of different antiviral therapies. Standard biphasic models well describe the viral load decline in the first 2–4 weeks of therapy, however the hypothesis of a constant clearance rate of the infected cells during longer treatment periods provides unrealistic estimates of the chance to reach a sustained virological response (SVR).

BACKGROUND: in type 2 diabetes, the maintenance of non-diabetic glycaemic levels has been shown to decrease the onset of long term complications and consequently their high management costs. In order to achieve and maintain normal blood glucose levels, lifestyle interventions are highly cost/effective, but require good compliance, strong motivation and efforts by the patients. For this reason, a majority of patients needs to start pharmacological therapy shortly after diagnosis. Rosiglitazone, an insulin-sensitising drug, is indicated for subjects with inadequate glycaemic control both as monotherapy, in those contraindicated to metformin, especially if overweight, and as combination therapy with metformin, sulphanilureas or both. OBJECTIVES: rosiglitazone offers clinical advantages over the alternatives, decreasing and/or postponing the need for insulin treatment. Its high acquisition cost may therefore be totally or partially offset by the reduction in future health care resources consumption, and by short-term practical advantages, such as the decrease in the need for blood glucose monitoring and of adverse events. Aim of this study was to investigate the impact of the use of rosiglitazone in eligible diabetic patients on the National Health System budget. METHODS: for this scope an analytic model was implemented, which pathway may be summarized as follows: a) estimate of the number type 2 diabetes patients living in Italy, grouped according to current therapeutic classes; b) estimate of the number of patients with inadequate glycaemic control for each subgroup; c) identification of patients eligible to rosiglitazone treatment; d) identification of the comparator strategy for each patient sub-group; e) comparison of costs for each couple of alternative options; f) calculation of budget impact. RESULTS: use of rosiglitazone monotherapy instead of sulphanilurea monotherapy induces a mild costs increase. Combination treatment with rosiglitazone added to metformin- or sulphanilurea- based therapies induces significant cost savings for the National Health System, related to lower resources consumption for glycaemic auto-monitoring and for hypoglycaemic events management, as compared to standard combination therapies. The hypothetical scenario in which all eligible patients are treated with rosiglitazone was estimated to induce net cost savings of about 260 millions Euro per year.

Bayesian statistic methods are facing a rapidly growing level of interest and acceptance in the field of health economics. The reasons of this success are probably to be found on the theoretical fundaments of the discipline that make these techniques more appealing to decision analysis. To this point should be added the modern IT progress that has developed different flexible and powerful statistical software framework. Among them probably one of the most noticeably is the BUGS language project and its standalone application for MS Windows WinBUGS. Scope of this paper is to introduce the subject and to show some interesting applications of WinBUGS in developing complex economical models based on Markov chains. The advantages of this approach reside on the elegance of the code produced and in its capability to easily develop probabilistic simulations. Moreover an example of the integration of bayesian inference models in a Markov model is shown. This last feature let the analyst conduce statistical analyses on the available sources of evidence and exploit them directly as inputs in the economic model.

BACKGROUND: Peginterferon beta-1a, injected every two weeks, is the first approved pegylated interferon beta-1a for the treatment of relapsing remitting multiple sclerosis (RRMS). The objective of this analysis was to estimate the economic impact due to the introduction of peginterferon beta-1a in Italy.METHODS: This analysis was conducted with a three-year time horizon with the support of a simple decision-analytic model adopting the perspective of the Italian National Healthcare Service (NHS). Healthcare costs sustained by the Italian NHS to manage the RRMS population (drug treatment, monitoring, relapse management, adverse events management) were calculated over 3 years and compared in two scenarios: the base scenario where interferons-beta and glatiramer acetate (GA) are used to treat RRMS patients, and an alternative scenario where peginterferon beta-1a can also be used to treat RRMS patients. The target population was approximately 35,500, 37,500 and 39,500 patients at year 1, 2 and 3 respectively, based on the published literature and market data. The efficacy of treatments was simulated as a reduction of relapse rates and was derived from a Network Meta-analysis. Unit costs were based on current prices and tariffs, and the published literature. A one-way sensitivity analysis was developed.RESULTS: According to current price and described assumptions, it was estimated that the introduction of peginterferon beta-1a would result in a decrease of total costs when compared with the base scenario. The cost in the base scenario was estimated to be € 321.5, € 339.7 and € 357.8 million in years 1, 2, and 3, respectively. In the alternative scenario, the same costs resulted in about € 321.1, € 338.6 and € 356.2 million, respectively. The cumulative budget impact over three years period was approximately a cost saving of € 3.1 million (about 0.3% saving).CONCLUSION: The adoption of peginterferon beta-1a for the treatment of RRMS would be viewed as economically sustainable by the Italian NHS.[Article in Italian]

BACKGROUND: Peginterferon beta-1a is indicated in adult patients for the treatment of relapsing remitting multiple sclerosis (RRMS). The efficacy and safety of peginterferon beta-1a was demonstrated in the placebo-controlled ADVANCE trial.OBJECTIVE: The objective of this study was to assess the cost-effectiveness of peginterferon beta-1a as compared with injectable first-line treatments for RRMS in Italy.METHODS: The cost-effectiveness analysis was developed through a Markov model with lifetime simulation in the perspective of the Italian National Healthcare Service (NHS). It was added an alternative scenario to take into account the Italian societal perspective. Outcomes were measured in terms of life years (LYs), quality adjusted life years (QALYs), lifetime costs and incremental cost-effectiveness ratio (ICER). The natural progression of the disease was informed by the published literature and previously published modelling exercises. The efficacy of treatments was simulated as reduction of disability progression (EDSS) and relapse rate. Efficacy data were derived from a published network meta-analysis. Unit costs were based on current prices and tariffs, and the published literature. A 3.5% discount rate was applied to costs and outcomes. One-way and probabilistic sensitivity analyses were developed and cost-effectiveness acceptability curves generated.RESULTS: Peginterferon beta-1a was more effective than the comparators in terms of survival (19.94 vs.19.68-19.81 discounted LYs, respectively), and QALYs (9.07 vs. 8.06 and 8.55 discounted QALY, respectively). In the perspective of the Italian NHS, the ICER was € 11,111/QALY vs. interferon beta-1a 30 µg, € 12,604/QALY vs. interferon beta-1a 22 µg, € 10,580/QALY and € 16,702/QALY vs. interferon beta-1b 250 µg and € 22,023/QALY vs. glatiramer acetate 20 mg. Peginterferon beta-1a dominated interferon beta-1a 44 µg. In the societal perspective, peginterferon beta-1a was dominant due to being more effective and with a lower social cost compared to first-line injectable treatments (interferon beta -1a, interferon beta-1b, glatiramer acetate) for RRMS. The outcomes of the sensitivity analyses confirmed the trend of the base case results.CONCLUSIONS: Peginterferon beta-1a shows a favourable pharmaco-economic profile for the treatment of RRMS. Even if an official threshold for the cost-effectiveness does not exist in Italy, the ICER values obtained were far below the commonly accepted thresholds (30,000-50,000 €/per QALY gained).[Article in Italian]

Analytic models are a powerful instrument to develop pharmacoeconomic analyses and their importance is growing as they are being increasingly used to make predictions of the consequences of a particular intervention. It is possible to group the most commonly used techniques in three families: decision trees, Markov chains and probabilistic simulation models. Only the last ones take into account a wide range of uncertainties and have the capability to make probabilistic predictions. Discrete-state, discrete-time Markov models are the most used technique, but have some limits due to their structural rigidity that can make appropriate representation of clinical reality difficult. First-order simulation of Markov models produces deterministic results and can be conveniently implemented in a matrix algebra formal framework. In order to take decision based on models prediction deterministic results are not sufficient and it is widely recognized the need to handle uncertainty in its various forms. The task could be accomplished with traditional (deterministic) and/or probabilistic sensitivity analysis. Both analyses provide complementary information on how the parameters and assumptions uncertainty spreads trough the model and are recommended by ISPOR (International Society for Pharmacoeconomics and Outcomes Research) modelling guidelines.

Current practice guidelines for the treatment of COPD recommend the use of combined inhaled corticosteroids and long-acting bronchodilators in severe and very severe patients (GOLD stages III and IV). OBJECTIVES: To analyze the economical and clinical impact of this recommendation, the affordability of its widespread application, as well as the relative pharmacoeconomical performance of the available options for severe and very severe COPD in Italy. METHODS: Published data on the Italian COPD population were fitted in a disease progression model based on a Markov chain representing severity stages and death. Alternative therapeutic options (salmeterol/ fluticasone - SF, formoterol/budesonide - FB, salmeterol alone - S, fluticasone alone - F and control - C) were represented as competing arms in a decision tree. Efficacy data from international trials were expressed in terms of risk reduction. Clinical parameters used were number of exacerbations and symptom-free days. Direct and indirect costs were considered and valued according to present prices and tarifs. The analyses were conducted from National Health System, societal and patient perspectives with time horizons of 1,5, and 10 years, and lifelong. RESULTS: The yearly total direct costs of treating COPD patients in Italy is estimated in approximately 7 billion Euro, with a mean cost/patient/year around 2,400 Euro. Mean survival of the cohort is 11,5 years. The C and F strategies are dominated (i.e. are associated with worse outcomes and higher costs) by all alternatives. S/F and F/B are the most effective strategies, with a slight clinical superiority of the latter, but are also marginally more expensive than S. Incremental cost/effectiveness of S/F vs. S is 679,55 Euro/avoided exacerbation and 3,31Euro/gained symptom-free day. CONCLUSIONS: The recommended use of combined inhaled corticosteroids and long-acting bronchodilators for severe and very severe COPD patients, as compared with current practice, has the potential of improving clinical outcomes without increasing health care costs.