Efgartigimod and Ravulizumab for Treating Acetylcholine Receptor Auto-antibody-Positive (AChR-Ab+) Generalized Myasthenia Gravis: Indirect Treatment Comparison.

INTRODUCTION: Efgartigimod and ravulizumab, both approved for treating acetylcholine receptor auto-antibody-positive (AChR-Ab+) generalized myasthenia gravis (gMG), have not been directly compared. This paper assessed comparative effects of efgartigimod vs. ravulizumab for treating adults with AChR-Ab+ gMG using indirect treatment comparison methods. METHODS: The matching-adjusted indirect comparison used data from two randomized trials of adult men and women. The ADAPT (efgartigimod vs. placebo; individual patient data available) population was reweighted to match the CHAMPION (ravulizumab vs. placebo; index study; aggregate data available) population. The relative effect of efgartigimod versus placebo was estimated in this reweighted population and compared with the observed ravulizumab versus placebo effect to estimate the efgartigimod versus ravulizumab effect. The outcomes were Myasthenia Gravis Activities of Daily Living (MG-ADL), Quantitative Myasthenia Gravis (QMG), and Myasthenia Gravis Quality of Life 15-item-revised scale (MG-QoL15r) assessed as cumulative effect (area under the curve; AUC) over 26 weeks (primary) and change from baseline at 4 weeks and time of best response (week 4 for efgartigimod; week 26 for ravulizumab). RESULTS: For MG-QoL15r, efgartigimod had a statistically significant improvement compared with ravulizumab over 26 weeks [mean difference (95% confidence interval): - 52.6 (- 103.0, - 2.3)], at week 4 [- 4.0 (- 6.6, - 1.4)], and at time of best response [- 3.9 (- 6.5, - 1.3)]. Efgartigimod had a statistically significant improvement over ravulizumab in MG-ADL at week 4 [- 1.9 (- 3.3, - 0.5)] and at time of best response [- 1.4 (- 2.8, 0.0)] and in QMG at week 4 [- 3.2 (- 5.2, - 1.2)] and at time of best response [- 3.0 (- 5.0, - 1.0)]. For AUC over 26 weeks, improvements were not significantly different between efgartigimod and ravulizumab for MG-ADL [- 8.7 (- 36.1, 18.8)] and QMG [- 13.7 (- 50.3, 22.9)]. CONCLUSION: Efgartigimod may provide a faster and greater improvement over 26 weeks in quality of life than ravulizumab in adults with AChR-Ab+ gMG. Efgartigimod showed faster improvements in MG-ADL and QMG than ravulizumab.

Association Between Myasthenia Gravis-Activities of Daily Living (MG-ADL) and EQ-5D-5L Utility Values: The Additional Effect of Efgartigimod on Utilities.

INTRODUCTION: For patients with generalized myasthenia gravis (gMG), the association between symptom severity, often measured with the Myasthenia Gravis Activities of Daily Living (MG-ADL) instrument, and utility values is unknown. METHODS: Data was analyzed from the phase 3 ADAPT trial, which included adult patients with gMG randomly assigned to treatment with efgartigimod + conventional therapy (EFG + CT) or placebo + CT (PBO + CT). MG-ADL total symptom scores and the EQ-5D-5L, a measure of health-related quality of life (HRQoL), were collected biweekly up to 26 weeks. Utility values were derived from the EQ-5D-5L data with the United Kingdom value set. Descriptive statistics were reported for MG-ADL and EQ-5D-5L at baseline and follow-up. A normal identity-link regression model estimated the association between utility and the eight MG-ADL items. A generalized estimating equations (GEE) model was estimated to predict utility based on the patient's MG-ADL score and treatment received. RESULTS: A total of 167 patients (84 EFG + CT, 83 PBO + CT) contributed 167 baseline and 2867 follow-up measurements of MG-ADL and EQ-5D-5L. EFG + CT-treated patients experienced more improvements than PBO + CT-treated patients in most MG-ADL items and EQ-5D-5L dimensions, with the largest improvements observed in chewing, brushing teeth/combing hair, eyelid droop (MG-ADL); self-care, usual activities, mobility (EQ-5D-5L). The regression model indicated that individual MG-ADL items contributed differently to utility values, with the largest impact from brushing teeth/combing hair, rising from a chair, chewing, and breathing. The GEE model showed that each unit improvement in MG-ADL led to a statistically significant utility increase of 0.0233 (p < 0.001). In addition, a statistically significant improvement of 0.0598 (p = 0.0079) in utility was found for patients in the EFG + CT group compared to the PBO + CT group. CONCLUSION: Among patients with gMG, improvements in MG-ADL were significantly associated with higher utility values. MG-ADL scores alone were not sufficient to capture the utility gained from efgartigimod therapy.

Indirect treatment comparisons of avapritinib versus midostaurin for patients with advanced systemic mastocytosis.

Objective: This research aimed to compare the relative efficacy of avapritinib versus midostaurin for patients with advanced systemic mastocytosis. Method: A systematic literature review was performed to identify relevant evidence. Unanchored matching-adjusted indirect comparisons were conducted for overall survival (OS), overall response rate (ORR) and complete remission (CR). Results: The systematic literature review identified the clinical trials EXPLORER and PATHFINDER (investigating avapritinib) and D2201 and A2213 (investigating midostaurin). The avapritinib versus midostaurin adjusted hazard ratio for OS was 0.44 (95% CI: 0.25-0.76), and the adjusted odds ratios for ORR and CR were 4.06 (95% CI: 3.09-5.33) and 9.56 (95% CI: 0.97-93.81), respectively. Conclusion: The results suggest that avapritinib improves survival and response (ORR and CR) compared with midostaurin.

Systemic mastocytosis is a rare blood disorder caused by the build-up of too many abnormal mast cells, a type of white blood cell, in the skin and organs. Patients with advanced systemic mastocytosis have a low life expectancy and limited treatment options. This research aimed to compare the effectiveness of two recent and innovative treatments (called avapritinib and midostaurin) in extending life expectancy and decreasing mast cells and organ damage. As avapritinib and midostaurin were not investigated in the same clinical studies, it was necessary to compare the two treatments using the results from studies of each individual treatment. The published evidence used to support this comparison was systematically searched for and consisted of four clinical studies: the EXPLORER and PATHFINDER studies (investigating avapritinib) and D2201 and A2213 studies (investigating midostaurin). An indirect comparison between the studies was made that adjusted for differences in key patient characteristics. The results suggest that compared with midostaurin, avapritinib has the potential to extend life expectancy and decrease disease burden.

Clinical efficacy comparison of avapritinib with other tyrosine kinase inhibitors in gastrointestinal stromal tumors with PDGFRA D842V mutation: a retrospective analysis of clinical trial and real-world data.

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 .

A comparative analysis of international health technology assessments for novel gene silencing therapies: patisiran and inotersen.

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.

Cost-analysis of persistent hyperkalaemia in non-dialysis chronic kidney disease patients under nephrology care in Italy.

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.

Cost Effectiveness of the Third-Generation Tyrosine Kinase Inhibitor (TKI) Ponatinib, vs. Second-Generation TKIs or Stem Cell Transplant, as Third-Line Treatment for Chronic-Phase Chronic Myeloid Leukemia.

BACKGROUND AND OBJECTIVES: Third-line treatment options for patients with chronic-phase chronic myeloid leukemia include tyrosine kinase inhibitors and allogeneic hematopoietic stem cell transplantation (alloHSCT). The objective of this study was to develop a Markov model with a lifetime time horizon to assess the cost effectiveness of ponatinib for third-line chronic-phase chronic myeloid leukemia vs. second-generation tyrosine kinase inhibitors (dasatinib, nilotinib, bosutinib) or alloHSCT from the public healthcare system perspective in Germany, Sweden, and Canada. METHODS: Clinical outcomes were derived from the literature, and from patient-level data (phase II PACE trial) for ponatinib. Resource use included drugs, alloHSCT, monitoring and follow-up, adverse events, and end-of-life care; costs were based on national tariffs. Quality-adjusted life-years (QALYs) were calculated using chronic myeloid leukemia health-state utilities from an international time-trade-off study. Costs and benefits were discounted at 3% per annum for Germany and Sweden, and 5% for Canada. RESULTS: Ponatinib yielded more discounted QALYs than any second-generation tyrosine kinase inhibitor/alloHSCT in all three countries, mainly owing to better response rates and longer durations of response. Incremental cost-effectiveness ratios for ponatinib vs. second-generation tyrosine kinase inhibitors were US$21,543-37,755/QALY in Germany, $24,018-38,227/QALY in Sweden, and $43,001-58,515/QALY in Canada. Ponatinib was dominant over alloHSCT in Germany, while incremental cost-effectiveness ratios for ponatinib vs. alloHSCT in Sweden and Canada were $715/QALY and $31,534/QALY, respectively. CONCLUSIONS: Ponatinib may improve outcomes (mainly because of higher response rates and longer response durations) at an acceptable cost level compared with other third-line treatment options for chronic-phase chronic myeloid leukemia in Germany, Sweden, and Canada; however, the lack of an indirect comparison is a limitation of our study.

Systematic review: economic evaluations of HCV screening in the direct-acting antivirals era.

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 $50 000 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.

Benefits and risks of ponatinib versus bosutinib following treatment failure of two prior tyrosine kinase inhibitors in patients with chronic phase chronic myeloid leukemia: a matching-adjusted indirect comparison.

OBJECTIVE: Comparing the benefit-risk profiles of ponatinib vs. bosutinib in third-line (3L) treatment of chronic phase chronic myeloid leukemia (CP-CML) is challenging because their pivotal trials lacked comparator arms. To characterize the overall benefit-risk profile in 3L CP-CML patients treated with bosutinib vs. ponatinib, a matching-adjusted indirect comparison (MAIC) was performed to compare efficacy outcomes and treatment duration after adjusting for trial subjects' baseline characteristics, and tolerability was assessed with an unadjusted comparison of study-drug discontinuation. METHODS: The MAIC was performed using published data from the pivotal bosutinib trial and the most recent individual-patient-level data on file from the pivotal ponatinib trial. RESULTS: Responses were more frequent and durable with ponatinib (n = 70 MAIC-adjusted) than with bosutinib (n = 119) - complete cytogenetic response (CCyR): 61% vs. 26%; Kaplan-Meier estimate of maintaining CCyR at 4 years: 89% vs. 54%. Median treatment duration was longer with ponatinib than with bosutinib: 38.4 vs. 8.6 months. Only 9% of ponatinib patients (n = 97 unadjusted) vs. 42% of bosutinib patients discontinued due to death, disease progression or unsatisfactory response; 19% vs. 24% discontinued due to adverse events. CONCLUSIONS: Based on these surrogate measures of patient benefit-risk profiles, ponatinib appears to provide a net overall benefit vs. bosutinib in 3L CP-CML.

A Decision-Analytic Model to Assess the Cost-Effectiveness of Etelcalcetide vs. Cinacalcet.

INTRODUCTION: 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. OBJECTIVE: The objective of this study was to develop a decision-analytic model for economic evaluation of etelcalcetide compared with cinacalcet. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Tocilizumab after a first-line with anti-TNF in rheumatoid arthritis: a cost-consequence analysis in the Italian setting.

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 <3.2) or in remission (DAS28-ESR <2.6). The model simulated the response to treatments, based on the Rotation Or Change (ROC) trial, the probability of discontinuation and switch to a 3rd-line biologic, and the transition to death. Time on treatment curves for 2nd-line biologics were derived from published Italian real-word data. Costs were estimated based on published sources and Italian prices and tariffs. RESULTS: The switch to tocilizumab after the failure of a first anti-TNF-α was more effective than a second anti-TNF-α, in terms of days in remission (224 vs. 114 days) and of days in LDA (345 vs. 193 days). The cost-consequence ratio with tocilizumab iv was 174 euros/day in remission and 113 euros/day in LDA. With tocilizumab sc the ratio was 181 euros/day in remission and 117 euros/day in LDA. The same ratios for the anti-TNF-α treatments ranged from 233 to Euro 320 euros per day in remission and from 138 to 190 euros per day in LDA. CONCLUSIONS: The switch to a different mechanism of action, namely tocilizumab, after the failure of a first anti-TNF-α agent seems a rational strategy for RA patients in the Italian setting.

Disease-Modifying Therapies for Multiple Sclerosis: A Systematic Literature Review of Cost-Effectiveness Studies.

INTRODUCTION AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Internationally, a large number of health economic assessments of DMTs in RRMS were available, yielding difficult to compare, and at times conflicting, results.

Exploring the potential value of improved care for secondary hyperparathyroidism with a novel calcimimetic therapy.

AIMS: 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. MATERIALS AND METHODS: 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. RESULTS: 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. LIMITATIONS: 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. CONCLUSIONS: This cost-effectiveness analysis, including scenarios to address uncertainties, allowed estimation of a value-based price range to aid reimbursement decisions in the US.

Cost-effectiveness analysis of pharmacokinetic-driven prophylaxis vs. standard prophylaxis in patients with severe haemophilia A.

: 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 5 197&OV0556; per patient-year. Pharmacokinetic-driven prophylaxis was preferable (i.e. more effective and less costly) compared with standard prophylaxis, with savings of 31 205&OV0556; 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.

Cost of persistent asthma in Italy.

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.

The Burden of Rheumatic Diseases: An Analysis of an Italian Administrative Database.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

The Cost of Relapsing-Remitting Multiple Sclerosis Patients Who Develop Neutralizing Antibodies during Interferon Beta Therapy.

BACKGROUND: 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. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Fluticasone furoate/Vilanterol 92/22 µg once-a-day vs Beclomethasone dipropionate/ Formoterol 100/6 µg b.i.d.: a 12-week cost analysis in mild-to-moderate asthma.

BACKGROUND: Asthma is a disease with high cost for the National Health Service. Two of the most recent LABA/ICS combinations for persistent bronchial asthma are Beclomethasone dipropionate/Formoterol (B/F) delivered via the Nexthaler device and Fluticasone furoate/Vilanterol (F/V) delivered via the Ellipta device. No comparison has been carried out yet in terms of cost analysis in asthma, to our knowledge. Aim of the present monocentric, observational, retrospective study was to calculate and compare the costs of mild-to-moderate asthma patients assuming B/F 100/6 µg b.i.d. to those of patients assuming F/V 92/22 µg once-a-day over a 12-week treatment period from the Italian National Health Service perspective. METHODS: Data were obtained automatically and anonymously from the institutional database of the Lung Unit of the Specialist Medical Centre (CEMS), Verona, Italy, UNI EN ISO 9001-2008 validated. FEV1 values, number of relapses, healthcare resources as hospitalizations due to asthma relapses, days of hospitalization, general practitioner (GP), specialist visits, and days of inactivity, were recorded over the study period together with the use of extra medications (systemic steroids and antibiotics). In order to compare the outcomes achieved in both groups, the propensity score matching method was used in STATA, and statistical significance was accepted for p < 0.05. RESULTS: Clinical data of 77 patients treated with B/F b.i.d (Group A) and of 40 patients treated with F/V 92/22 µg once-a-day (Group B) were selected. The PS-matching process, designed as matching on the baseline covariates, gender, age, FEV1 and comorbidities, returned a cohort of 40 group A patients of the entire cohort matched with 40 patients of group B, fully comparable for demographics and clinical characteristics. In the PS-matched cohort, the mean (±SE) number of relapses per patient during the follow-up was 0.53 (±0.12) in group A and 0.28 (±0.07) in group B. In group A, n = 25 (62.50 %), n = 9 (22.50 %), and n = 6 (15 %) patients had 0, 1, 2 relapses, respectively. In group B, n = 29 (72.50 %), and n = 11 (27.50 %) had 0 and 1 relapse, respectively. Over the study period, the average number of hospitalizations per patient was 0.15 (±0.06), with 0.28 (±0.12) days of hospitalization in group A, and 0.08 (±0.04) with 0.08 (±0.04) days of hospitalization in group B, respectively. The difference between the two groups in terms of FEV1(L) improvement vs baseline was 0.11 in favour of group B (p = 0.007). When results were compared, the improvement in lung function obtained in group B proved significantly higher both in terms of absolute FEV1 and of FEV1 % predicted. The mean (±SE) cost of hospitalizations per patient was € 345.30 (±133.23) in group A and € 172.65 (±98.18) in group B, respectively, with a mean not significant difference of - € 172.65 in favour of group B (p = 0.9). In particular, the mean (±SE) cost for visits per patient was € 26.82 (±3.73) in group A and € 11.36 (±2.30) in group B (p = 0.002), and the mean cost for rescue medications per patient was € 35.24 (±6.93) in group A, and € 18.73 (±3.38) in group B, respectively (p = 0.05). CONCLUSIONS: Even if both ICS/LABA combinations were checked over a limited period of time, they seem characterized by a different profile in terms of effect on lung function and economic impact on mild-to-moderate asthma. The once-daily inhalation of combined Fluticasone furoate/Vilanterol 92/22 µg showed the potential for enhanced clinical outcomes and reduced costs when compared to Beclomethasone dipropionate/Formoterol 100/6 µg b.i.d.

Cost-effectiveness of Chloride-liberal versus Chloriderestrictive Intravenous Fluids among Patients Hospitalized in the United States.

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.

Costs of illness analysis in Italian patients with chronic obstructive pulmonary disease (COPD): an update.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality worldwide, and its epidemiological, clinical, and socioeconomic impact is progressively increasing. A first estimate of the economic burden of COPD in Italy was conducted in 2008 (the SIRIO [Social Impact of Respiratory Integrated Outcomes] study). The aim of the present study is to provide an updated picture of the COPD economic burden in Italy. METHODS: Sequential patients presenting at the specialist center for the first time during the period 2008-2012 and with record file complete (demographic, clinical, lung function, and therapeutic data; health care resources consumed in the 12 months before the enrollment and for the 3 subsequent years) were selected from the institutional database. RESULTS: Two hundred and seventy-five COPD patients fitting the inclusion criteria were selected (226 males; mean age: 70.9 years [standard deviation: ±8.4 years]; 45.8% were from the north, 25.1% from central Italy, and 29.1% from south Italy). COPD-related average costs per patient in the 12 months before enrollment were as follows: hospitalization: €1,970; outpatient care: €463; pharmaceutical: €499; and indirect costs: €358. Average direct costs and total societal costs were €2,932 and €3,291, respectively. Direct cost was €2,461 (hospitalization: €1,570; outpatient: €344; and pharmaceutical: €547) in the first year of follow-up, while total societal cost was €2,707. No significant difference was reported in any cost category between sexes. CONCLUSION: The therapeutic approach followed in a specialist center, based on the application of clinical guidelines, has been shown to be a highly effective investment for the long-term management of COPD. A small increase of pharmaceutical costs per year allowed a substantial saving in terms of hospitalizations, costs related to outpatient services, and indirect costs.