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Abstract Background Avapritinib, 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). Methods This 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. Results Fifty-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. Conclusions In this indirect, retrospective analysis, avapritinib demonstrated more durable survival outcomes compared with other TKIs in patients with unresectable/metastatic PDGFRA D842V-mutant GIST. Trial registration The NAVIGATOR trial was registered at ClinicalTrials.gov as per July 2015, Identifier: NCT02508532 .

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.

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.

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]

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]

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]

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]

BACKGROUND: Empagliflozin is the most recent molecule in the SGLT-2i class, new antidiabetic drugs that reduce renal glucose absorption by determining the excretion in the urine. The high prevalence of T2D, the chronicity of the condition and the severe economic and social burden caused by the disease, impose the need for a careful health economic assessment on each therapeutic innovation in this area. AIM: The aim of this study was to assess the budget impact of adopting empagliflozin in the diabetic population currently treated with sulfonylureas and potentially eligible for treatment with SGLT-2i. METHODS: The budget impact analysis was conducted from the perspective of the Italian National Health Service over a period of three years, through an analytic model developed in MS Excel. The target population was estimated in about 170,000 patients currently treated with sulfonylureas, based on the growth forecasts of the Italian population, epidemiological estimates and drug-use information available in the literature on diabetes in Italy. In the base case was assumed a replacement rate of sulfonylureas equal to 10%, 20% and 30% respectively at the first, second and third year of analysis. A scenario analysis was considered assuming a constant uptake of 100% since the first year. The following direct healthcare costs were considered: 1) acquisition of antidiabetic drugs as the main therapy and as rescue therapy; 2) self-monitoring of blood glucose; 3) management of severe hypoglycemic events and 4) management of major cardiovascular events. Clinical effectiveness data was based on the published literature and unit costs were derived from current prices and tariffs. Oneway sensitivity analysis was developed to assess the impact of input’s uncertainty on the overall result. RESULTS: The base case analysis presented a substantially neutral impact on the budget. The 3-year cumulative impact was -454.337 €, corresponding to a 0.1% saving. This means that the replacement of sulphonylureas with empagliflozin determines an increase in acquisition costs of drugs, which is entirely offset by the reduction in costs of self-monitoring of blood glucose, management of hypoglycemic events and cardiovascular events. The scenario analysis, based on the assumption of a full substitution of sulphonylureas with empagliflozin at the first year, yielded a more enhanced savings. The cumulative impact was -2.269.517 €, corresponding to a 0.6% saving. CONCLUSIONS: The present study shows that the replacement of sulfonylureas (a class of generic products) with empagliflozin, motivated by the advantageous efficacy and safety profile, can take place optimizing healthcare expenditure for the management of DT2. [In Italian]

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.

Budget impact analysis of empagliflozin in T2D patients with a previous cardiovascular diseaseIntroductionThe EMPA-REG OUTCOME study demonstrated that empagliflozin is effective in reducing cardiovascular morbidity and mortality in T2D patients with high risk linked to a previous cardiovascular condition. The objective of this study is the budget impact analysis of the use of empagliflozin in this population in Italy.MethodsThe analysis was conducted from the cost perspective of the Italian NHS with a 3-year time horizon. The target population, defined as T2D patients with a known cardiovascular disease, was estimated based on epidemiologic and market data. An uptake of empagliflozin growing from 10% to 30% was considered to add up or substitute combinations of metformin, insulin, glitazones and DPP-4. The uptake of 80-100% was considered to substitute sulfonylureas and repaglinide. Costs, including drugs, glycaemia monitoring, management of severe hypoglycaemia events, and cardiovascular and renal events, were estimated based on published literature and current tariffs.ResultsThe target population was estimated in 243,693 in the first year. The incremental cost for drugs (17.6 million Euro) is entirely offset by the savings in glycaemia monitoring (8.1 million Euro), cardiovascular and renal events (8.8 million Euro) and severe hypoglycaemic events (3.1 million Euro), with a net saving of 2.3 million Euro, approximately corresponding to -0.7% of the total expenditure. The cumulative budget impact in the 3 years was 4.9 million Euro (-0.5%).ConclusionsThe progressive adoption of empagliflozin to treat T2D patients with known cardiovascular disease in Italy, would provide significant clinical benefit without entailing additional expense for the Italian NHS.

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.

**Background:** Patients developing acute kidney injury (AKI) during critical illness or major surgery are at risk for renal sequelae such as costly and invasive acute renal replacement therapy (RRT) and chronic dialysis (CD). Rates of renal injury may be reduced with use of chloride-restrictive intravenous (IV) resuscitation fluids instead of chloride-liberal fluids. **Objectives:** To compare the cost-effectiveness of chloride-restrictive versus chloride-liberal crystalloid fluids used during fluid resuscitation or for the maintenance of hydration among patients hospitalized in the US for critical illnesses or major surgery. **Methods:** Clinical outcomes and costs for a simulated patient cohort (starting age 60 years) receiving either chloride-restrictive or chloride-liberal crystalloids were estimated using a decision tree for the first 90-day period after IV fluid initiation followed by a Markov model over the remainder of the cohort lifespan. Outcomes modeled in the decision tree were AKI development, recovery from AKI, progression to acute RRT, progression to CD, and death. Health states included in the Markov model were dialysis free without prior AKI, dialysis-free following AKI, CD, and death. Estimates of clinical parameters were taken from a recent meta-analysis, other published studies, and the US Renal Data System. Direct healthcare costs (in 2015 USD) were included for IV fluids, RRT, and CD. US-normalized health-state utilities were used to calculate quality-adjusted life years (QALYs). **Results:** In the cohort of 100 patients, AKI was predicted to develop in the first 90 days in 36 patients receiving chloride-liberal crystalloids versus 22 receiving chloride-restrictive crystalloids. Higher costs of chloride-restrictive crystalloids were offset by savings from avoided renal adverse events. Chloride-liberal crystalloids were dominant over chloride-restrictive crystalloids, gaining 93.5 life-years and 81.4 QALYs while saving $298 576 over the cohort lifespan. One-way sensitivity analyses indicated results were most sensitive to the relative risk for AKI development and relatively insensitive to fluid cost. In probabilistic sensitivity analyses with 1000 iterations, chloride-restrictive crystalloids were dominant in 94.7% of iterations, with incremental cost-effectiveness ratios below $50 000/QALY in 99.6%. **Conclusions:** This analysis predicts improved patient survival and fewer renal complications with chloriderestrictive IV fluids, yielding net savings versus chloride-liberal fluids. Results require confirmation in adequately powered head-to-head randomized trials.

Background: Chronic Obstructive Pulmonary Disease (COPD) affects about 4.5% of the Italian population, representing one of most burdensome public health problems. Literature data report an annual health care expenditure ranging between € 1,300 and € 4,500 per patient, of which drug costs are a limited share. In 1998 the WHO started GOLD program in order to ameliorate COPD patient management. As a part of his program, periodically updated guidelines are produced with the aim of defining an efficient diagnostic-therapeutic pathway managed by a multidisciplinary team and based on the optimization of the use of drugs and diagnostic tests and the reduction of exposure to risk factors. Objective: to estimate the economic consequences of GOLD guidelines adoption in the Italian clinical practice. Methods: a decision analytic model capable of calculating the impact on the National Health Service budget of an ameliorated adherence to GOLD guidelines (GOLD GL strategy), basing on the needed variations in health care strategies on a defined patient cohort treated with the current approach (CURRENT strategy). The simulation runs on a cohort representing Italian COPD patients over 45 years who transit through 5 Markov health states (4 GOLD stages and death), according to patient characteristics (age, gender, FEV1), with a time horizon of 3 years. Stage-specific drug consumption of the CURRENT strategy is based on data of 3,113 patients collected by three Health Local Units involved in a larger clinical audit project. The consumption of other health resources, i.e. medical visits and inpatient care, is estimated based on a multicentre observational Italian study. The GOLD GL strategy includes spirometry-based staging on the totality of the simulated patients, the development of a therapeutic strategy including the redefinition of pharmacological therapy based on guideline recommendations and experts opinion, and variation of other health resources consumption based on observational data. Costs of health care resources are calculated based on published micro-costing analysis and current prices and tariffs. Results: the model estimates an adjunctive cost of about 19 million of Euros with the GOLD GL strategy, just for the the spirometry-based restaging of about 40% of the over 1 million and 250 thousand prevalent Italian COPD patients. Furthermore, in the first year of the analysis, the redefinition of the best clinical management strategy for all patients would cost about 100 million Euros, which are to be added to the more than 320 million Euros associated with adaptation of the GOLD stage specific pharmacological therapy, consisting mainly in a higher usage of long-acting beta agonist/corticosteroid combinations, only partially offset by the lower prescription of corticosteroid alone. Based on Italian observational data, the consumption of other health care resources with the GOLD GL strategy is reduced by about 44%, reflected in an estimated cost saving of more than 850 millions of Euros. For the first analysis year, the net cost saving associated with full GOLD guideline adoption is estimated equal to 410 millions of Euros; this value decreases by 11% and 21% respectively in the second and third years. Conclusion: our model estimates that the adoption of GOLD guidelines in the Italian clinical practice is associated to an average cost saving of about 300 Euros per patient/year.

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.

Sugammadex is a modified cyclodextrin which acts by encapsulating and inactivating the neuromuscular blocking agents (NMBAs) rocuronium and vecuronium, used to induce relaxation of skeletal muscles during surgery and to facilitate endotracheal intubation. The procedure of reversal of the block at the end of surgery can influence the time to discharge from the operating room and post-operative residual curarization (PORC) incidence, which is related to an increased rate of adverse respiratory events in the post-anaesthesia care unit. Cholinesterase inhibitors are frequently used to reverse neuromuscular block, but their use is associated with potential cardiovascular and respiratory side-effects. The recommended dose-range for sugammadex is 2-16 mg/kg, depending on the level of block: the dose is approximately 2 mg/kg for reversal of moderate blockade, 4 mg/kg for deep blockade and 16 mg/kg for the immediate reversal of a neuromuscular blockade as early as 3 minutes after 1-1.2 mg/kg of rocuronium. Four pivotal, phase III trials studied sugammadex in routine reversal of moderate, deep neuromuscular block and in the immediate reversal of rocuronium-induced block. In all the cases the drug demonstrated of being significantly more efficient than other reversal strategies, providing a faster reversal than the most used anticholinesterase comparator neostigmine. Sugammadex also appeared to have an acceptable safety profile. Acquisition cost of sugammadex is greater than that of neostigmine, but cost-savings related to the reduced theatre time and to the reduced incidence of PORC episodes can offset it. A Budget Impact analysis in the perspective of the hospital has been conducted for the Italian setting resulting in a total cost-save of 7,420 € for one year of activity. In conclusion, sugammadex appears to be a valuable innovation in anesthesiology. This drug represents a safe and effective alternative to anticholinesterase agents.

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: 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.

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 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.

Introduction: prostatic cancer is the second more frequent cancer in Italy (after lung cancer) and is the third cancer-related death cause. Age is the principal risk factor and, given the ageing process undergoing in the Italian population, it seems clear that the public sanitary expenditure to treat the disease is bound to increase, arising the need to perform pharmacoeconomic evaluations of the therapeutic strategies available. Methods: we performed a cost/utility analysis, through a Markov model, of several hormonal therapies in patients with advanced prostate cancer who underwent radical prostatectomy, from the biochemical recurrence to death. Nine androgen suppression therapies were considered: orchiectomy, two nonsteroidal antiandrogens (NSAA), four luteinizing hormone-releasing hormone (LHRH) agonists, cyproterone acetate and the association of a NSAA and a LHRH (BAT). In the simulation the androgen suppression therapies were started at the PSA recurrence and never stopped until death. The model used the Italian NHS prospective and a time horizon corresponding to patient’s lifetime. Drug costs were calculated for each therapy, considering the less costly brand. Results: all the considered therapies produced a life expectancy (LE) of about 12 life years (LYs) with a small variability ranging from 12.3 LYs for BAT (the most effective) to 11.37 LYs for NSAA-flutamide (the least effective). Quality adjusted life expectancy ranged from 9.98 QALYs for BAT to 9.28 QALYs for NSAA-flutamide. The average cost per patient presented a more enhanced variability, from 12,538 Euro for orchiectomy to 59,496 Euro for NSAA-bicalutamide. Among all the alternatives orchiectomy resulted the most cost/effective alternative with a cost/utility ratio of about 1,300 Euro/QALY. In the LHRH-agonists class leuprorelin was the most cost/effective with about 2,200 Euro/QALY. A one-way sensitivity analysis showed a substantial stability of the results. Conclusions: BAT resulted the most effective therapy, but also the one associated with the highest expected cost. Orchiectomy was marginally less effective but at the same time generated the lowest cost and, thus, represented the most cost/effective strategy. Nonetheless, its application in actual clinical practice is difficult and quite always refused by patients. Among the class of LHRH-agonists leuprorelin (considering the less costly brand, Eligard®) dominated the alternatives and, thus, could provide an excellent therapeutic strategy.

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.

Relapsing Remitting Multiple Sclerosis (RRMS) patients treated with interferon beta (IFN beta) can develop neutralizing antibodies (NAbs) that reduce treatment efficacy. Several clinical studies explored the association of NAb+ status with increased disease activity.The aim of this study was to estimate the cost of RRMS patients who develop NAbs while treated with IFN beta by the Italian National Healthcare Service (NHS) and the Italian Society perspectives.The clinical data derived from a published observational study on 567 RRMS Italian patients treated with IFN beta. The management cost data derived from the published literature. Cost data were inflated to Euro 2014.The annual direct cost to treat a patient was estimated in €15,428 in the NAb+ cohort and €14,317 in the NAb- cohort. The annual societal cost was estimated in €33,890 and €30,790 in NAb+ and NAb- patients, respectively. The cost increase related to the NAb+ status was €3,100 in the Italian societal perspective and €1,111 in the Italian NHS perspective.The results of this economic evaluation suggest the presence of an association between NAb+ status and increased costs for the management of RRMS in Italy. Further pharmacoeconomic research will be needed to confirm this first result.

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: 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.

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.

Type 2 diabetes mellitus (DM) and peripheral arterial disease (PAD) are two very relevant cardiovascular (CV) risk factors, which can often be found concurrently in the same patient. The DAVID trial, a double-blind, randomized, aspirin(ASA)-controlled study, has demonstrated that the use of picotamide, a thromboxane A2 synthase and receptor dual inhibitor, is associated with lesser CV morbidity and mortality in this type of patients in comparison to ASA, considered the standard antiplatelet agent. In order to estimate clinical and economic impacts of picotamide in the Italian health care setting, we developed a pharmacoeconomic model based on clinical data from DAVID and national economic parameters and demographics. The base case scenario, which reflects current prices and reimbursement policy (i.e. ASA fully paid for, picotamide out-of-pocket for patients) yielded an incremental cost/effectiveness ratio (ICER) of about 8,500 euro/year of life (YOL) saved, which falls below conventionally adopted willingness to pay thresholds. This cost, however, is totally born by the patient, while the savings on health care expenditures for avoided events (and less ASA) benefit the national health service (NHS). These results may help the physician in explaining the consequences of this choice to his/her patients, facilitating a fully-informed choice. The availability of a theoretical model allowed to explore some alternative scenarios, that indicate that the ICER can be further lowered and the economical burden better distributed through policy changes. In conclusion, the pharmacoeconomic model indicated that picotamide is likely to be a cost/effective option for CV mortality and morbidity prevention in patients with concurrent type 2 DM and PAD and that the level of adoption of this strategy will depend on willingness to pay and policy priorities of the NHS and patients themselves.

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.

Cardiovascular disease (CVD) remains one of the leading causes of mortality and morbidity worldwide. Since several pharmacological approaches are available for the reduction of incidence and severity of cardiovascular events and health resources in modern managed care systems are limited, the evaluation of the clinical and economical consequences of any treatment is very valuable for decison-makers and physicians. In this article we present a flexible pharmacoeconomic model that permits the calculation of the marginal costeffectiveness of cardiovascular prevention with ramipril, a drug of the class of ACE-inhibitors. The clinical data used for the modelization are derived from the HOPE (Heart Outcomes Prevention Evaluation) study, a landmark cardiovascular prevention study that showed how the benefits of ACE-inhibition with ramipril go beyond the effects on blood pressure, while Italian epidemiological, demographic and economical data make the results appliable to the Italian population. The model, structured as a decision tree comparing the alternatives “to treat” or “not to treat” with Markow chains at the terminal nodes, calculates the marginal cost-effectiveness of the preventive treatment in terms of cost/year of live saved. The model is characterized by high flexibility, as it allows health decision-makers to set epidemiological and economical data in order to reflect the local population at high risk for developing cardiovascular diseas. The model was tested on a high risk population, formed by all acute myocardial infarction survivors in Italy, and indicated that life-long treatment of this patients would yield significant clinical benefits, with a cost/ effectiveness of 3,932 euro/year of life saved. This value is well below the standards that are considered acceptable, and offsprings from the partial offset of pharmaceutical costs caused by the reduction in the expenses for diagnosis and treatment of the cardiovascular events avoided with the preventive therapy.