Characteristics and Drug Utilization of Patients with Hereditary Angioedema in Italy, a Real-World Analysis.

This real-world analysis investigated the characteristics and treatment patterns of patients with hereditary angioedema (HAE) in Italy using the administrative data of health units across Italy. Patients were identified via exemption code or HAE-specific treatments (thus, all known forms, type I, II and, III, were included). The index date was that of first prescription of HAE treatments within the inclusion period (01/2010-06/2021) or of the date of exemption. The number of HAE patients included was 148 (43.2% male, mean age 43.3 years). Gastrointestinal disorders affected 36.5% patients, hypertension affected 28.4%, hypercholesterolemia affected 11.5%, and depression affected 9.5%. The frequent gastrointestinal involvement was further confirmed by the use of antiemetics and systemic antihistamines that doubled after the index date. Among patients enrolled by treatment (n = 125), n = 105 (84%) were receiving a treatment for acute attacks. This analysis provided insights into the characterization of patients with HAE and their management in Italian clinical practice, suggesting that an unmet therapeutic need could be present for such patients in terms of the clinical burden.

Comparison of Direct Oral Anticoagulant Use for the Treatment of Non-Valvular Atrial Fibrillation in Pivotal Clinical Trials vs. the Real-World Setting: A Population-Based Study from Southern Italy.

Patients enrolled into pivotal randomized controlled trials (RCTs) may differ substantially from those treated in a real-world (RW) setting, which may result in a different benefit-risk profile. The aim of the study was to assess the external validity of pivotal RCT findings concerning direct oral anticoagulants (DOACs) for the treatment of nonvalvular atrial fibrillation (NVAF) by comparing patients recruited in RCTs to those treated with DOACs registered in a southern Italian local health unit (LHU) in the years 2013-2017. The Palermo LHU claims database was used to describe the baseline characteristics of incident DOAC users (washout > 1 year) with NVAF compared with those of enrolled patients in DOAC pivotal RCTs. In the RW, DOAC treatment discontinuation was calculated during the follow-up and compared with DOAC treatment discontinuation of enrolled patients in DOAC pivotal RCTs. Rates of effectiveness and safety outcomes during the follow-up were calculated in an unmatched and in a simulated RCT population, by matching individual incidental RW and RCT DOAC users (excluding edoxaban users) on age, sex, and CHADS2 score. Overall, 42,336 and 7092 incident DOAC users with NVAF were identified from pivotal RCTs and from the RW setting, respectively. In RCTs, DOAC use was more common among males (62.6%) compared with an almost equal sex distribution in the RW. RCT patients were younger (mean age ± standard deviation: 70.7 ± 9.2 years) than RW patients (76.0 ± 8.6 years). Compared with RCTs, a higher proportion of RW dabigatran users (30.4% vs. 19.6%) and a lower proportion of RW apixaban (15.9% vs. 25.3%) and rivaroxaban (20.4% vs. 23.7%) users discontinued the treatment during the follow-up (p-value < 0.001). The rate of ischemic stroke was lower in RW high-dose dabigatran users (unmatched/-matched population: 0.40-0.11% per year) than in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) population (0.93% per year). Major bleeding rates were lower in RW users than in RCT users. In conclusion, except for dabigatran, a lower proportion of DOAC discontinuers was observed in the real-world than in pivotal RCT settings. This study provides reassurance to practicing physicians that DOAC use appears to be effective in stroke prevention and is likely safer in RW patients than in RCT enrolled patients. These results may be related to a lower burden of comorbidities despite more advanced age in the RW population compared to the pivotal RCT population.

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.

Real World Use of Antidiabetic Drugs in the Years 2011-2017: A Population-Based Study from Southern Italy.

Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia. The availability of new antidiabetic drugs (ADs) has led to complex treatment patterns and to changes in the patterns of specific drug utilization. The aim of this population-based study was to describe the pattern of antidiabetic drugs (ADs) use in Southern Italy in the years 2011-2017, in relation to the updated type 2 diabetes mellitus (T2DM) therapy guidelines. A retrospective cohort study was conducted on T2DM patients using data from the Palermo Local Health Unit (LHU) claims database and diabetologist registry. The first-line treatment was investigated and incident treatments were identified and characterized at baseline in terms of demographics, complications, comorbidities, concomitant drugs and clinical parameters. Persistence to AD treatment was also evaluated. During the study period, one-third of first ever ADs users started the treatment with ADs other than metformin, in contrast to guideline recommendations. Among 151,711 incident AD treatments, the male to female ratio was 1.0 and the median age was 66 (57-75) years. More than half (55.0%) of incident treatments discontinued the therapy during the first year of treatment. In Italy, general practitioners (GPs) can only prescribe first-generation ADs, while the prescription of more recently marketed ADs, such as GLP-1RA, DPP4i and SGLT2i, is restricted to diabetologists only, based on a therapeutic plan. The role of GPs in the management of T2DM in Italy should be re-evaluated.

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.

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.

Non-persistence risk and health care resource utilization of Italian patients with non-valvular atrial fibrillation

The aim of this study is to compare discontinuation risk and health care resource utilization between vitamin K antagonists (VKAs) and non-vitamin K antagonist oral anticoagulants (NOACs) in newly treated patients with non-valvular atrial fibrillation (NVAF). Based on administrative databases of five Italian Local Healthcare Units, all patients with a discharge diagnosis of NVAF between 2011 and 2014 were selected. Among them, the incident users of NOACs and VKAs in 2014 were followed-up to from the first prescription date to the occurrence of anyone of the following events: a 90-day gap in therapy, switch to a different molecule or add-on of a different molecule into the regimen, death of patient, end of follow-up (December 2015). All-cause hospitalizations, outpatient visits and examinations within the persistence period were also evaluated. The final cohort was composed of 2909 and 765 incident users of VKA and NOACs, respectively. Cox regression to model time to non-persistence within 12 months showed a 62% reduction in risk of drug discontinuation in NOAC patients compared to VKA patients (HR,0.38 [0.33-0.44]). In the adjusted analyses with warfarin as reference, apixaban patients (HR, 0.35 [0.24-0.50]) had the lowest risk of non-persistence, followed by rivaroxoban (HR, 0.42 [0.33-0.54]) and dabigatran users (HR, 0.51 [0.43-0.61]). The mean total numbers of all-cause hospitalization records in 12-month persistent patients were significantly less in NOACs users compared with VKA users (0.36 vs 0.47, p-value:0.03). Similarly, the differences in the mean numbers of all-cause visits and examinations were statistically significant between VKA and NOAC patients, who registered on average 2.33 vs 1.84 visits (p-value: 0.01) and 24.4 vs 9.2 exams referrals (p-value: <0.0001), respectively. NOACs showed a better profile in terms of both resource utilization and persistence compared with VKAs. In particular, apixaban returned the lowest risk of discontinuation than dabigatran and rivaroxaban.

The impact of polypharmacy and drug interactions among the elderly population in Western Sicily, Italy.

AIM: Primary endpoint was to report polypharmacy distribution in the general population vs ≥65 years old people and to examine the frequency of drug-drug interactions (DDIs) in the Health Local Unit of Palermo, Italy, in relationship with patients' age. METHODS: Drug prescription data for the year 2014 were extracted from the database of the Local Health Unit of Palermo Province, Italy. Patients were divided into five age groups (0-13, 14-64, 65-69, 70-74, and ≥75 year old). The detection of potential DDIs in polypharmacy profiles was performed with NavFarma software (Infologic srl, Padova, Italia), with DDI classification provided by tool Micromedex Drug Reax (Truven Health Analitics, Michigan, USA). RESULTS: We analyzed data of 1,324,641 patients, and 15,801,191 medical prescription were recorded; of these, 11,337,796 regarded chronic conditions. The drug prescriptions reached the highest values in the 65-69 and 70-74 age groups (p = 0.005 and p = 0.008 vs age 14-64 respectively). An overall amount of 6,094,373 DDIs were detected, of which 47,173 were contraindicated. Median number of DDIs was higher in 65-69 and 70-74 age groups (p = 0.008 and p = 0.012 vs age 14-64, respectively). Regarding contraindicated DDIs a significant difference was detected comparing 14-64 vs ≥65 age groups (p = 0.010 vs 65-69 group, p = 0.005 vs 70-74 group and ≥75 group). CONCLUSIONS: Polypharmacy is a phenomenon acquiring increasing dimensions also in our province. It interests particularly the older subjects, and assumes a dramatic accent when it is put in relationship with the frequency of DDIs. A proactive vigilance about potential life threatening drug interactions is mandatory.

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.