Direct healthcare costs of chronic kidney disease management in Italy: What cost-savings can be achieved with higher biosimilar uptake and more appropriate use of erythropoiesis-stimulating agents?

PURPOSE: Erythropoiesis-stimulating agents (ESAs), are used for treating chronic kidney disease (CKD)-related anemia, contributing to CKD costs. The study was aimed at investigating direct healthcare costs of CKD patients treated with ESAs and the potential savings achievable by increasing the use of biosimilars and preventing inappropriate ESA use. METHODS: A multi-center, cohort study was conducted using claims databases of five large Italian geographic areas. Yearly mean direct healthcare costs per patient were estimated, stratifying by CKD stage. The total yearly cost and potential savings related to ESA use were estimated: (a) considering 25/50/75% of originator ESA substitution with biosimilars; (b) eliminating inappropriate ESA dispensing. RESULTS: During the study period, the ESA-related yearly mean cost represented 17% of total yearly costs in stage I-III, decreasing to 13% in stage IV-V and 6% in dialysis. Among originator users, assuming a 25% of biosimilar uptake, the annual cost-savings of ESA treatment would represent 10.5% of total ESA costs in CKD stage I-V and 7.7% in dialysis. Among incident ESA users for which hemoglobin levels were available, 9% started inappropriately ESA treatment, increasing to 62.0% during the first year of maintenance therapy. Hypothesizing prevention of the first inappropriate ESA dispensing, the total yearly cost-savings would amount to €35 772, increasing to €167 641 eliminating the inappropriate dispensing during maintenance therapy. CONCLUSIONS: Higher use of lowest cost ESA, prevention of inappropriate ESA use as well as other strategies aimed at slowing down the progressive renal impairment are essential for minimizing clinical and economic burden of CKD.

Association Between Intravitreal Aflibercept and Serious Non-ocular Haemorrhage Compared with Intravitreal Ranibizumab: A Multicentre Observational Cohort Study.

INTRODUCTION: Intravitreal anti-vascular endothelial growth factor (VEGF) drugs aflibercept and ranibizumab are used in neovascular retinal diseases but may be associated with non-ocular haemorrhage. AIMS: Our objective was to compare the risk of non-ocular haemorrhage with intravitreal aflibercept versus intravitreal ranibizumab and with individual intravitreal anti-VEGFs versus intravitreal dexamethasone. METHODS: A retrospective cohort study was conducted using four Italian claims databases, covering 18 million inhabitants from 2011 to 2016. Incident aflibercept users were matched 1:4 to incident ranibizumab users. The outcome was incident non-ocular haemorrhage requiring hospitalisation. Incidence per 1000 person-years (PYs) was estimated. Patients were followed for 180 days using an intention-to-treat (ITT) approach. An as-treated (AT) approach was also employed, using grace periods of 60 or 90 days. Analyses were repeated for aflibercept versus dexamethasone and ranibizumab versus dexamethasone. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. RESULTS: We identified incident users of intravitreal ranibizumab (n = 21,766), aflibercept (n = 3150) and dexamethasone (n = 3900). The incidence of haemorrhage was four events per 1000 PYs for each drug. Aflibercept was not associated with increased risk versus ranibizumab at 180 days (HR 0.97 [95% CI 0.37-2.56]). Results were consistent in the AT analysis (HR 1.19 [95% CI 0.52-2.75]). No increased risk was found for aflibercept and ranibizumab at 180 days versus dexamethasone (HR 0.70 [95% CI 0.30-2.60] and HR 0.67 [95% CI 0.33-1.38], respectively). CONCLUSION: No association was identified between intravitreal aflibercept and non-ocular haemorrhage versus ranibizumab. A comparable risk for these intravitreal anti-VEGFs and intravitreal dexamethasone was observed.

How Have Intravitreal Anti-VEGF and Dexamethasone Implant Been Used in Italy? A Multiregional, Population-Based Study in the Years 2010-2016.

PURPOSE: To describe intravitreal anti-VEGF drug and dexamethasone use in four Italian regions. METHODS: Four regional claims databases were used to measure drug prevalence, compare dosing intervals to those recommended in the summary of product characteristics (SPC), and identify switchers. Bilateral treatment and diabetic macular edema (DME) coding algorithms were validated, linking claims with a sample of prospectively collected ophthalmological data. RESULTS: Overall, 41,836 patients received ≥1 study drug in 2010-2016 (4.8 per 10,000 persons). In 2016, anti-VEGF drug use ranged from 0.8 (Basilicata) to 5.7 (Lombardy) per 10,000 persons while intravitreal dexamethasone use ranged from 0.2 (Basilicata) to 1.4 (Lombardy) per 10,000 persons. Overall, 40,815 persons were incident users of study drugs. Among incident users with ≥1 year of follow-up (N = 30,745), 16.0% (N = 30,745), 16.0% (N = 30,745), 16.0% (. CONCLUSION: Study drug use increased over time in Lombardy, Basilicata, Calabria, and Sicily, despite a large heterogeneity in prevalence of use across regions. Drug treatment appeared to be partly in line with SPC, suggesting that improvement in clinical practice may be needed to maximize drug benefits.

In Search of Predictors of Switching Between Erythropoiesis-Stimulating Agents in Clinical Practice: A Multi-Regional Cohort Study.

BACKGROUND AND OBJECTIVES: Switching between different erythropoiesis-stimulating agents (ESAs) during the first year of therapy is frequent (15-20%), much more so toward reference products than biosimilars. The objectives of this study were to investigate the frequency and identify the potential predictors of switching between biosimilar and originator ESAs during the first year of treatment in patients with chronic kidney disease (CKD), or chemotherapy-related anemia from six large Italian geographic areas in the years 2009-2015. METHODS: A retrospective cohort study was conducted using six Italian regional claims databases (≥ 13 million inhabitants) during 2009-2015. Among incident epoetin users, the frequency of single, multiple, and backward switch during the first year of treatment was evaluated. Using frailty Cox models, potential predictors of first switch were identified. All analyses were stratified by the main indications for use. RESULTS: Among 102,240 incident epoetin users, 15,853 (15.5%) switched to another epoetin during the first year of therapy; only 18% of these switched to biosimilars. Single switch was more common (62.2% of the switchers) than multiple (23.5%) or backward switch (14.3%). In cancer, the cumulative number of transfusions and iron preparations dispensed, as well as hyperparathyroidism, were predictors of switching. In CKD, the cumulative number of transfusions, number of vitamin A/D preparations dispensed, and CKD severity increased the probability of switching. CONCLUSIONS: Switching between ESAs was frequent in both CKD and cancer patients. The number of cumulative transfusions and severity of disease seemed to affect the switch.

Antibiotic Consumption and Resistance during a 3-Year Period in Sicily, Southern Italy.

Antimicrobial resistance (AMR) is one of the biggest issues facing global public health. In 2017, Italy adopted its first National Action Plan on Antimicrobial Resistance 2017-2020, which works through the synergy between national, regional, and local levels. In the framework of a Regional Action Plan on healthcare-associated infections and AMR prevention, the Sicilian Health Authority of the Sicilian Region, Southern Italy, has implemented a surveillance system of antibiotic consumption in hospitals, in the community, and of resistance rates (RRs) in hospital settings. Data on antibiotic consumption and on antibiotic RRs have been collected from 2015 to 2017 from pharmacies and laboratories of participating hospitals and from community, respectively. Data on antibiotic consumption showed that the most consumed antibiotics in hospitals were fluoroquinolones in 2015, penicillin in 2016, and beta-lactams in 2017. From 2015 to 2017, data on Klebsiella pneumoniae showed significant increasing RRs to all antibiotic classes, except to carbapenems. RRs of third-generation cephalosporins and carbapenems Escherichia coli showed significant decreasing trends. RRs of the other microorganisms did not change significantly during the study period. The results from the present study show that in Sicily, the use of antibiotics and RRs for selected microorganisms are at a high level. Immediate strategies are needed to decrease the inappropriate usage of antibiotics and control the spread of AMR.

Effectiveness and Safety of Switching Originator and Biosimilar Epoetins in Patients with Chronic Kidney Disease in a Large-Scale Italian Cohort Study.

INTRODUCTION: Real-world data on the comparative effectiveness and safety of switching among different epoetins (including originators and biosimilars) are limited. In light of current debate about interchangeability, prescribers, some patient groups and decision makers are calling for additional post-marketing evidence on the clinical effects of switching between originator and biosimilar epoetins in chronic kidney disease (CKD) patients. OBJECTIVE: The objective of this study was to evaluate the effectiveness and safety of switching versus non-switching and of switching from originator/biosimilar epoetin alpha (ESA α) to any other epoetin in CKD patients. METHODS: An observational, record-linkage, multi-database, retrospective cohort study was carried out in four Italian geographical areas. All subjects with at least one ESA α dispensing between 1 January 2009 and 31 December 2015 were retrieved. Switching was defined as any transition between originator/biosimilar ESA α to any other epoetin in a series of two consecutive prescriptions up to 2 years. Switchers were matched 1:1 with non-switchers by baseline propensity score and by duration of ESA α treatment. Switchers and non-switchers were followed up from switching date to a maximum of 1 year. Lack of effectiveness and safety of switching versus non-switching were evaluated through Cox regression models (hazard ratio [HR], 95% confidence interval [CI]). A direct comparison between the two switcher categories (switchers from originator/biosimilar ESA α to any other epoetin) was also performed. RESULTS: Overall, 14,400 incident users of ESA α for anaemia due to CKD (61.4% originator, 38.6% biosimilar) were available for analysis. During the follow-up, we found no differences on effectiveness (HR 1.02, 95% CI 0.79-1.31 originators; HR 1.16, 95% CI 0.75-1.79 biosimilars) and safety outcomes (HR 1.08, 95% CI 0.77-1.50 originators; HR 1.20, 95% CI 0.66-2.21 biosimilars) between switchers and non-switchers of ESA α. Cumulative probabilities of recording an adverse event, either in terms of lack of effectiveness or safety issue, were the same for two switching categories CONCLUSIONS: In this large-scale Italian observational multi-database study, switching versus non-switching as well as switching from biosimilar/originator ESA α to any other epoetin in CKD patients is not associated with any effectiveness and safety outcomes.

Role of healthcare databases and registries for surveillance of orphan drugs in the real-world setting: the Italian case study.

INTRODUCTION: Orphan drugs are medicines intended to treat, prevent, or diagnose a rare and serious condition. The collection of pre-marketing safety and efficacy data for orphan drugs is very challenging for several reasons related to the rarity of the diseases. This highlights the need for robust post-marketing evidence generation. Real-world data sources, such as claims databases, electronic healthcare records, and disease and drug registers, have an important role in studying orphan drugs. The availability and usefulness of such resources vary from country to country. AREAS COVERED: A detailed description of the available real-world data sources and their contribution to generating post-marketing evidence on orphan drug benefit-risk profile in Italy is provided. EXPERT OPINION: Despite their considerable potential for rare disease research, the available Italian data sources are currently under-used and require further harmonization of data collection. The establishment of large structured and integrated nationwide data sources, tailored to respond to both research as well as regulatory requirements, is necessary to provide clinically useful information on orphan drugs as well. Such data sources should also be more accessible at the loco-regional, national and international level.

Pattern of Use of Biosimilar and Originator Somatropin in Italy: A Population-Based Multiple Databases Study During the Years 2009-2014.

PURPOSE: Somatropin [recombinant growth hormone (rGH)] is approved in children and adults for several conditions involving growth disturbances and the corresponding biosimilar is available in Italy since 2006. No population-based data are available on the pattern of rGH use in Italian clinical practice. This study aimed at exploring the pattern of biosimilar and originator rGH use in six Italian centers, where different policy interventions promoted biosimilar use. METHODS: This population-based, drug-utilization study was conducted in the years 2009-2014, using administrative databases of Umbria, Tuscany, and Lazio Regions and Local Health Units of Caserta, Treviso, and Palermo. Naïve rGH users were characterized, and prevalence of use and discontinuation were assessed over time. RESULTS: Among 6,785 patients treated with rGH during the study years, 4,493 (66.2%) were naïve users (males/females = 1.3), mostly affected by GH deficiency. The prevalence of rGH use increased from 2009 to 2010, remaining stable thereafter, but it was heterogeneous across centers (twofold higher prevalence of use in center n.2 than centers n.4 and 1 in 2014). Biosimilar rGH uptake increased over time but was low (7.8% in 2014) and heterogeneous as well. Discontinuation of rGH therapy occurred in 54.0% of naïve users, more frequently in females than males (58.1 vs. 50.9%). During the first year of treatment, discontinuation was frequent (39.9%), but no statistically significant differences were observed in treatment persistence for biosimilar vs. originator rGH (p > 0.05). CONCLUSION: Geographical heterogeneity in the prevalence of rGH use was observed. Similarly, the biosimilar rGH uptake was low and variable across centers. Post-marketing monitoring is required to continuously monitor the benefit-risk profile of rGH, thus guaranteeing greater savings than only promoting lowest cost rGH.

How did the Introduction of Biosimilar Filgrastim Influence the Prescribing Pattern of Granulocyte Colony-Stimulating Factors? Results from a Multicentre, Population-Based Study, from Five Italian Centres in the Years 2009-2014.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs) are biological products for which the main indication of use is chemotherapy-induced neutropenia. Biosimilars of G-CSFs have been available in Europe since 2007. OBJECTIVE: The objective of this study was to investigate the prescribing pattern of G-CSFs in five Italian centres using different healthcare policy interventions to promote the use of biosimilars in routine care. METHODS: This retrospective, population-based drug utilization study was conducted during the years 2009-2014 using the administrative databases of the Caserta, Treviso and Palermo Local Health Units (LHUs) and the Tuscany and Umbria regions. G-CSF users were characterized and the prevalence of use, proportion of biosimilar users and switching pattern of different G-CSFs were evaluated over time and across centres. RESULTS: Overall, 30,247 patients were treated with G-CSFs in the years 2009-2014, of which 29,083 (96.2 %) were naïve users. The overall prevalence of G-CSF use increased from 0.8 per 1000 inhabitants in 2009 to 1.1 per 1000 in 2014. An increase in the proportion of the use of the biosimilar filgrastim by the total G-CSF users was observed in all centres: from 0.2 % (2009) to 66.2 % (2014). However, heterogeneity across different centres was reported, with the largest increase in Treviso LHU (from 0 to 89.1 % from 2009 to 2014). During the first year of treatment, switching between different G-CSFs was frequent (20.3 %). CONCLUSIONS: Heterogeneity in the use of G-CSF and, in particular, biosimilar filgrastim across different Italian centres was observed, probably due to different regional healthcare policy interventions. During the first year of treatment, switching between different G-CSFs was frequent. Considering the impact of biological drugs on pharmaceutical expenses, it is necessary to harmonize healthcare policies promoting the use of biological drugs with the lowest cost.

How Much Are Biosimilars Used in Clinical Practice? A Retrospective Italian Population-Based Study of Erythropoiesis-Stimulating Agents in the Years 2009-2013.

PURPOSE: To explore the prescription patterns of erythropoiesis-stimulating agents (ESAs) in four large Italian geographic areas, where different health policy interventions to promote biosimilar use in routine care are undertaken. METHODS: A retrospective drug utilization study was conducted during the years 2009-2013. The data sources were the administrative databases of the Tuscany region and of the Caserta, Palermo, and Treviso Local Health Units (LHUs). The characteristics, prevalence, and switching patterns of different ESAs (biosimilars and reference products), stratified by indication for use, were calculated over time and across centers. RESULTS: Overall, 49,491 patients were treated with ESAs during the years 2009-2013 in the four centers. Of these, 41,286 patients (83.4 %) were naive users. The prevalence of ESA use increased from 2.9 to 3.4 per 1000 inhabitants in the years 2009-2011 but decreased thereafter (3.0 per 1000 in 2013). Moreover, the proportion of biosimilar users increased overall from 1.8 % in 2010 to 33.6 % in 2013, with larger increase in Treviso (from 0.0 to 45.0 %) and Tuscany (from 0.7 to 37.6 %) than in Caserta (from 7.5 to 22.9 %) and Palermo (from 0.0 to 27.7 %). Switching between different ESAs during the first year of therapy was frequent (17.0 %), much more toward reference products than toward biosimilars. CONCLUSION: Overall, the prevalence of ESA use decreased slightly, while use of biosimilar ESAs, especially in naive patients, increased significantly but to different extents in these four large Italian geographic areas. Switching between different ESAs during the first year of treatment was very frequent, which may affect pharmacovigilance monitoring. New strategies are necessary to further improve market penetration of low-cost medicines, such as biosimilars, and also to harmonize effective health policy interventions that aim to reduce pharmaceutical expenses and optimize patient benefit across all regions.

How much are biosimilars used in southern Italy?: a retrospective analysis of epoetin utilization in the local health unit of Messina in the years 2010-2011.

BACKGROUND: Epoetins are one of the three biologics for which biosimilars are available in Italy. So far, there is a lack of Italian national/regional longitudinal data about epoetin use. OBJECTIVE: The aim of this study was to evaluate the prescribing pattern of epoetins (reference products and biosimilars) in a Local Health Unit (LHU) of Southern Italy in recent years. METHODS: A retrospective drug utilization study was conducted during the period 1 January 2010 - 31 May 2011. The data source was the dispensing database of the Messina LHU, which contains anonymized data about dispensed drugs (including epoetins) that are prescribed by specialists to the residents in the catchment area. Indication of use and prescribed dosage of epoetins were derived by the therapeutic plans filled in by specialists and linked to drug dispensing records. Prevalence of epoetin use in the province of Messina (653 810 inhabitants) in 2010 was calculated. Furthermore, frequency analyses by sex, age, indication of use of epoetin users, as well as measurement of volume of use (defined daily dose [DDD]/1000/day) and expenditure of epoetins in 2010 were also performed. Analysis of the switching pattern between different reference products and biosimilar epoetins was performed. RESULTS: Overall, 4288 patients were treated with epoetins during the study period (mean age ± SD: 74.2 ± 13.7; females: 52%). Darbepoetin alpha and reference product epoetin alpha accounted overall for 79.8% of epoetin users, while biosimilars of epoetin alpha accounted for 0.9%. Among 1247 epoetin users for whom the therapeutic plan was revised, 1065 (85.4%) were treated because of anemia due to chronic kidney disease and 158 (12.6%) because of chemotherapy-induced anemia. In 2010, prevalence of epoetin use was 5.5 (95% CI 5.3, 5.7) per 1000 inhabitants in the province of Messina. The volume of use and related expenditure for epoetins was 3.58 DDD/1000 inhabitants/day and Euro 5 572 457 (about Euro 8.50 per capita/day) in 2010. Switching between different epoetins was very frequent (21.8% of users) but switching from reference products to biosimilars was very rare. CONCLUSIONS: Epoetins are frequently dispensed to residents in the province of Messina, mainly for the treatment of chronic kidney disease-related anemia, with a relevant impact on the pharmaceutical expenditure covered by the National Health System. Use of biosimilar products is very low in both naïve patients and in those who switch from other reference product epoetins.