Effectiveness of homologous/heterologous booster COVID-19 vaccination schedules against severe illness in general population and clinical subgroups in three European countries.

Using 4 data-sources (Spain, Italy, United Kingdom) data and a 1:1 matched cohort study, we aimed to estimate vaccine effectiveness (VE) in preventing SARS-CoV-2 infections with hospitalisations (±30 days) and death (±56 days) in general population and clinical subgroups with homologous/heterologous booster schedules (Comirnaty-BNT and Spikevax-MOD original COVID-19 vaccines) by comparison with unboosted individuals, during Delta and beginning of Omicron variants. Hazard Ratio (HR, by Cox models) and VE ([1-HR]*100) were calculated by inverse probability weights. Between December 2020-February 2022, in adults without prior SARS-CoV-2 infection, we matched 5.5 million people (>1 million with immunodeficiency, 343,727 with cancer) with a booster (3rd) dose by considering doses 1 and 2 vaccine brands and calendar time, age, sex, region, and comorbidities (immunodeficiency, cancer, severe renal disease, transplant recipient, Down Syndrome). We studied booster doses of BNT and MOD administered after doses 1 and 2 with BNT, MOD, or Oxford-AstraZeneca during a median follow-up between 9 and 16 weeks. BNT or MOD showed VE ranging from 70 to 86% across data sources as heterologous 3rd doses, whereas it was 42-88% as homologous 3rd doses. Depending on the severity and available follow-up, 3rd-dose effectiveness lasted between 1 and 5 months. In people with immunodeficiency and cancer, protection across data sources was detected with both heterologous (VE = 54-83%) and homologous (VE = 49-80%) 3rd doses. Overall, both heterologous and homologous 3rd doses with BTN or MOD showed additional protection against the severe effects of SARS-CoV-2 infections for the general population and for patients at potentially high risk of severe COVID-19 (elderly, people with immunodeficiency and cancer) in comparison with two doses schemes during Delta or early Omicron periods. The early VE after vaccination may be due to less testing among vaccinated pairs and unknown confounders, deserving cautious interpretation. The VE wane over time needs further in-depth research to properly envisage when or whether a booster of those vaccines should be administered.

Impact of the 2018 revised Pregnancy Prevention Programme by the European Medicines Agency on the use of oral retinoids in females of childbearing age in Denmark, Italy, Netherlands, and Spain: an interrupted time series analysis.

Background: In March 2018, the European pregnancy prevention programme for oral retinoids was updated as part of risk minimisation measures (RMM), emphasising their contraindication in pregnant women. Objective: To measure the impact of the 2018 revision of the RMMs in Europe by assessing the utilisation patterns of isotretinoin, alitretinoin and acitretin, contraceptive measures, pregnancy testing, discontinuation, and pregnancy occurrence concomitantly with a retinoid prescription. Methods: An interrupted time series (ITS) analysis to compare level and trend changes after the risk minimisation measures implementation was conducted on a cohort of females of childbearing age (12-55 years of age) from January 2010 to December 2020, derived from six electronic health data sources in four countries: Denmark, Netherlands, Spain, and Italy. Monthly utilisation figures (incidence rates [IR], prevalence rates [PR] and proportions) of oral retinoids were calculated, as well as discontinuation rates, contraception coverage, pregnancy testing, and rates of exposed pregnancies to oral retinoids, before and after the 2018 RMMs. Results: From 10,714,182 females of child-bearing age, 88,992 used an oral retinoid at any point during the study period (mean age 18.9-22.2 years old). We found non-significant level and trend changes in incidence or prevalence of retinoid use in females of child-bearing age after the 2018 RMMs. The reason of discontinuation was unknown in >95% of cases. Contraception use showed a significant increase trend in Spain; for other databases this information was limited. Pregnancy testing was hardly recorded thus was not possible to model ITS analyses. After the 2018 RMM, rates of pregnancy occurrence during retinoid use, and start of a retinoid during a pregnancy varied from 0.0 to 0.4, and from 0.2 to 0.8, respectively. Conclusion: This study shows a limited impact of the 2018 RMMs on oral retinoids utilisation patterns among females of child-bearing age in four European countries. Pregnancies still occur during retinoid use, and oral retinoids are still prescribed to pregnant women. Contraception and pregnancy testing information was limited in most databases. Regulators, policymakers, prescribers, and researchers must rethink implementation strategies to avoid any pregnancy becoming temporarily related to retinoid use.

Testing of Coding Algorithms for Inflammatory Bowel Disease Identification, as Indication for Use of Biological Drugs, Using a Claims Database from Southern Italy.

Background: Inflammatory bowel diseases (IBDs), Crohn's disease (CD) and ulcerative colitis (UC), are chronic diseases that have been increasingly treated with biological drugs in recent years. Newly developed coding algorithms for IBD identification using claims databases are needed to improve post-marketing surveillance of biological drugs. Objective: To test algorithms to identify CD and UC, as indication for use of biological drugs approved for IBD treatment, using a claims database. Methods: Data were extracted from the Caserta Local Health Unit database between 2015 and 2018. CD/UC diagnoses reported by specialists in electronic therapeutic plans (ETPs) were considered as gold standard. Five algorithms were developed based on ICD-9-CM codes as primary cause of hospital admissions, exemption from healthcare service co-payment codes and drugs dispensing with only indication for CD/UC. The accuracy was assessed by sensitivity (Se), specificity (Sp), positive (PPV) and negative predicted values (NPV) along with computation of the Youden Index and F-score. Results: In the study period, 1205 subjects received at least one biological drug dispensing approved for IBD and 134 (11.1%) received ≥1 ETP with IBD as use indication. Patients with CD and CU were 83 (61.9%) and 51 (38.1%), respectively. Sensitivity of the different algorithms ranged from 71.1% (95% CI: 60.1-80.5) to 98.8 (95% CI: 93.5-100.0) for CD and from 64.7% (95% CI: 50.1-77.6) to 94.1 (95% CI: 83.8-98.8) for UC, while specificity was always higher than 91%. The best CD algorithm was "Algorithm 3", based on hospital CD diagnosis code OR CD exemption code OR [IBD exemption code AND dispensing of non-biological drugs with only CD indication] (Se: 98.8%; Sp: 97.2%; PPV: 84.5%, NPV: 99.8%), achieving the highest diagnostic accuracy (Youden Index=0.960). The best UC algorithm was "Algorithm 3", based on specific hospital UC diagnosis code OR UC exemption code OR [IBD exemption code AND golimumab dispensing] OR dispensing of non-biological drugs with only UC indication (Se: 94.1%; Sp: 91.6%; PPV: 50.0%; NPV: 99.4%), and achieving the highest diagnostic accuracy (Youden Index=0.857). Conclusion: In a population-based claims database, newly coding algorithms including diagnostic and exemption codes plus specific drug dispensing yielded highly accurate identification of CD and UC as distinct indication for biological drug use.

Real-world patient characteristics and use of disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis: a cross-national study.

INTRODUCTION: Rheumatoid arthritis (RA) is associated with significant morbidity and economic burden. This study aimed to compare baseline characteristics and patterns of anti-inflammatory drug use and disease-modifying anti-rheumatic drug (DMARD) use among patients with RA in Southern Italy versus the United States. METHOD: Using Caserta Local Health Unit (Italy) and Optum's de-identified Clinformatics® Data Mart (United States) claims databases, patients with ≥ 2 diagnosis codes for RA during the study period (Caserta: 2010-2018; Optum: 2010-2019) were identified. Baseline patient characteristics, as well as proportion of RA patients untreated/treated with NSAIDs/glucocorticoids/conventional DMARDs (csDMARDs)/biological/targeted synthetic DMARDs (b/tsDMARDs) during the first year of follow-up, and the proportion of RA patients with ≥ 1 switch/add-on between the first and the second year of follow-up, were calculated. These analyses were then stratified by age group (< 65; ≥ 65). RESULTS: A total of 9227 RA patients from Caserta and 195,951 from Optum databases were identified (two-thirds were females). During the first year of follow-up, 45.9% RA patients from Optum versus 79.9% from Caserta were exclusively treated with NSAIDs/glucocorticoids; 17.2% versus 11.3% from Optum and Caserta, respectively, were treated with csDMARDs, mostly methotrexate or hydroxychloroquine in both cohorts. Compared to 0.6% of RA patients from Caserta, 3.2% of the Optum cohort received ≥ 1 b/tsDMARD dispensing. Moreover, 61,655 (33.7%) patients from Optum cohort remained untreated compared to 748 (8.3%) patients from the Caserta cohort. The subgroup analyses stratified by age showed that 42,989 (39.8%) of elderly RA patients were untreated compared to 18,666 (24.9%) young adult RA patients in Optum during the first year of follow-up. Moreover, a higher proportion of young adult RA patients was treated with b/tsDMARDs, with and without csDMARDs, compared to elderly RA patients (Optum<65: 6.4%; Optum≥65: 1.0%; P-value < 0.001; Caserta<65: 0.8%; Caserta≥65: 0.1%; P-value < 0.001). Among RA patients untreated during the first year after ID, 41.2% and 48.4% RA patients from Caserta and Optum, respectively, received NSAIDs, glucocorticoids, and cs/b/tsDMARDs within the second year of follow-up. Stratifying the analysis by age groups, 50.6% of untreated young RA patients received study drug dispensing within the second year of follow-up, compared to only 36.7% of elderly RA patients in Optum. Interestingly, more young adult RA patients treated with csDMARDs during the first year after ID received a therapy escalation to b/tsDMARD within the second year after ID in both cohorts, compared to elderly RA patients (Optum<65: 7.8%; Optum≥65: 1.8%; Caserta<65: 3.2%; Caserta≥65: 0.6%). CONCLUSIONS: Most of RA patients, with heterogeneous baseline characteristics in Optum and Caserta cohorts, were treated with anti-inflammatory/csDMARDs rather than bDMARDs/tsDMARDs during the first year post-diagnosis, especially in elderly RA patients, suggesting a need for better understanding and dealing with barriers in the use of these agents for RA patients. Key Points • Substantial heterogeneity in baseline characteristics and access to bDMARD or tsDMARD drugs between RA patients from the United States and Italy exists. • Most of RA patients seem to be treated with anti-inflammatory/csDMARD drugs rather than bDMARD/tsDMARD drugs during the first year post-diagnosis. • RA treatment escalation is less frequent in old RA patients than in young adult RA patients. • An appropriate use of DMARDs should be considered to achieve RA disease remission or low disease activity.

Are Patients with Psoriasis and Psoriatic Arthritis Undertreated? A Population-Based Study from Southern Italy.

This study aimed to explore the pattern of use of different treatment lines in psoriasis (PsO) and psoriatic arthritis (PsA) patients from Southern Italy. A retrospective cohort study was performed during the years 2010-2018 using data from the Caserta Local Health Unit (LHU) claims database. All of the PsO or PsA patients were identified. The proportion of PsO/PsA patients untreated or treated with ≥1 drug classes (i.e., non-disease-modifying antirheumatic drugs (non-DMARDs), conventional synthetic DMARDs (csDMARDs), biological drugs (bDMARDs) or targeted synthetic small molecules (tsDMARDs)) was calculated in the years 2016-2018. Among the bDMARD users, the median times from the first registered PsO/PsA diagnosis/from the first csDMARD to the first bDMARD were calculated. Overall, 10,296 (1.1%) and 1724 (0.2%) PsO and PsA patients were identified. More than half of the PsO patients (N = 5301; 51.6%) and 15% of the PsA patients (N = 251) were not treated with any drug. A very low proportion of PsO patients (N = 121; 1.2%) received csDMARDs/bDMARDs dispensing. Instead, 538 (32.2%) PsA patients were treated with bDMARDs. The median times from the first diagnosis to the first bDMARD dispensing were 54.0 (Q1-Q3: 30.5-72.2) and 13.3 (Q1-Q3: 3.1-43.9) months in the PsO and PsA patients, respectively. The median time from the first csDMARD to the first bDMARD dispensing was shorter in the PsO [9.2 months (Q1-Q3: 5.5-30.0)] than in the PsA [14.5 months (Q1-Q3: 8.6-33.5)] patients. A potential undertreatment of PsO (much less for PsA) in an LHU from Southern Italy, with a particularly low use of more recently marketed drugs, such as biological ones, was shown.

Characteristics and Absolute Survival of Metastatic Colorectal Cancer Patients Treated With Biologics: A Real-World Data Analysis From Three European Countries.

Introduction: Biologics were approved for the treatment of advanced colorectal cancer (CRC) based on favorable benefit-risk-assessments from randomized controlled trials (RCTs), but evidence on their use in the real-world setting is scarce. Based on descriptive analyses we therefore aimed to assess characteristics and survival of CRC patients treated with biologics using large healthcare databases from three European countries (Netherlands, Italy, Germany). Methods: We included CRC patients treated with a biologic in 2010 or 2014 and characterized them regarding age, sex, comorbidities, and absolute survival. Results: Among 4,758 patients, the mean age ranged from 64.8 to 66.8 years, the majority was male, and comorbidities used as exclusion criteria in RCTs were coded in up to 30% of these patients. The proportion of bevacizumab users decreased between 2010 (72-93%) and 2014 (63-85%). In 2014, the absolute 12-month survival in new users was 64% (95% CI 51-77%), 56% (30-80%), and 61% (58-63%) in the Dutch, Italian, and German database, respectively, varying by age and comorbidity. Conclusions: Our study suggests that in the real-world setting, CRC patients treated with biologics are older and less selected regarding comorbidities compared to patients in RCTs, potentially explaining the relatively low 12-month survival we found. Treatment decisions in the real-world setting may require careful evaluation given that the risk-benefit ratio may vary depending on age and co-existing conditions.

COVID-19 Patient Management in Outpatient Setting: A Population-Based Study from Southern Italy.

Evidence on treatments for early-stage COVID-19 in outpatient setting is sparse. We explored the pattern of use of drugs prescribed for COVID-19 outpatients' management in Southern Italy in the period February 2020-January 2021. This population-based cohort study was conducted using COVID-19 surveillance registry from Caserta Local Health Unit, which was linked to claims databases from the same catchment area. The date of SARS-CoV-2 infection diagnosis was the index date (ID). We evaluated demographic and clinical characteristics of the study drug users and the pattern of use of drugs prescribed for outpatient COVID-19 management. Overall, 40,030 patients were included in the analyses, with a median (IQR) age of 44 (27-58) years. More than half of the included patients were asymptomatic at the ID. Overall, during the study period, 720 (1.8%) patients died due to COVID-19. Azithromycin and glucocorticoids were the most frequently prescribed drugs, while oxygen was the less frequently prescribed therapy. The cumulative rate of recovery from COVID-19 was 84.2% at 30 days from ID and it was lower among older patients. In this study we documented that the drug prescribing patterns for COVID-19 treatment in an outpatient setting from Southern Italy was not supported from current evidence on beneficial therapies for early treatment of COVID-19, thus highlighting the need to implement strategies for improving appropriate drug prescribing in general practice.

Analgesic drug use in elderly persons: A population-based study in Southern Italy.

INTRODUCTION: Analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs), weak and strong opioids are commonly used among elderly persons. The aim of this study was to describe the demographic and clinical characteristics of elderly analgesic users and to measure the frequency of analgesic use, including the frequency of potentially inappropriate analgesic use. METHODS: The Arianna database was used to carry out this study. This database contains prescription data with associated indication of use for 1,076,486 inhabitants registered with their general practitioners (GPs) in the Caserta Local Health Unit (Caserta district, Campania region in Italy). A cohort of persons aged ≥65 years old with >1 year of database history having at least one analgesic drug (NSAIDs, strong or weak opioids) between 2010 and 2014 were identified. The date of the first analgesic prescription in the study period was considered the index date (ID). RESULTS: From a source population of 1,076,486 persons, 116,486 elderly persons were identified. Of these, 94,820 elderly persons received at least one analgesic drug: 36.6% were incident NSAID users (N = 36,629), while 13.2% were incident weak opioid users (N = 12,485) and 8.1% were incident strong opioid users (N = 7,658). In terms of inappropriate analgesic use, 9.2% (N = 10,763) of all elderly users were prescribed ketorolac/indomethacin inappropriately, since these drugs should not be prescribed to elderly persons. Furthermore, at least half all elderly persons with chronic kidney disease or congestive heart failure were prescribed NSAIDs, while these drugs should be avoided. CONCLUSION: Analgesics are commonly used inappropriately among elderly persons, suggesting that prescribing practice in the catchment area may yet be improved.

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.

Gender Differences in Outpatient Pediatric Drug Utilization: A Cohort Study From Southern Italy.

Objective: The aim of this retrospective population-based cohort study is to in-depth investigate gender-specific drug utilization pattern in pediatric outpatient population. Methods: By using a large administrative database of the Local Health Unit of Caserta (Southern Italy), a pediatric cohort from the birth to 18 years was observed over 6 years (from 1st January 2010 to 31st December 2015). Yearly prevalence of drug use per 100 inhabitants as well as the median number of prescriptions was stratifying by gender. Prevalence of acute and recurrent use of the most frequently used active substances was calculated for the year 2015. Results: A decreasing trend in prevalence of drug use (-3.2%, with a reduction of median number of drugs dispensed) was observed in children for both sexes, from 2010 to 2015. In 2015, the drug classes most commonly used among children of any age were modestly but consistently prescribed more to males than to females: systemic anti-infective drugs (M = 43.5%; F = 42.3%), respiratory tract drugs (M = 29.0%; F = 26.1%), and hormones (M = 13.1%; F = 11.3%). Irrespective of gender, beclomethasone was the most utilized active substance in the first 2 years of life, while thereafter amoxicillin/clavulanate in combination. Conclusions: In a large population of pediatric outpatients no major difference was seen between genders, although commonly used drug classes; in particular, antibiotics, respiratory tract drugs and Hormones with corticosteroids for systemic use prescribed modestly but consistently to larger extent in males than females.