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The Respiratory Syncytial Virus (RSV) is considered the leading cause of lower respiratory tract infections (LRTI) in children aged < 2 years. In high-risk children, including preterm infants, or in children with bronchopulmonary dysplasia (BPD) and infants with congenital heart diseases (CHD), RSV infections may lead to severe consequences that often require hospitalizations. The typical seasonality of RSV is going through some changes and as consequence the healthcare management of serious infections is facing some difficulties. In this context and in light of the worldwide economic, political and healthcare debate around treatment of RSV infections, this article aims to inform physicians and healthcare professionals about evidence regarding the two drugs licensed for passive prophylaxis against RSV, namely palivizumab and nirsevimab. According to the 1998 IMpact study, palivizumab administration (5 monthly doses) was able to reduce the incidence of RSV hospitalizations in infants born preterm and in those with BPD. However, over the years, several studies found questionable cost-effectiveness evidence regarding the use of palivizumab in preterm infants born at ≥ 29 weeks of gestation. Differently from palivizumab, one single dose of nirsevimab is able to protect over an entire RSV season. This drug was able to reduce hospitalizations and medically attended RSV-associated LRTI in infants born preterm and without comorbidities, but none similar efficacy was found in reducing hospitalizations in healthy infants born at term (born at ≥ 35 weeks of gestation). As such, while future interventions in the clinical management of RSV infections and related consequences are warranted, new evidence about nirsevimab and palivizumab use will be essential to define which population will benefit the most from passive prophylaxis.

IntroductionSafe and effective pharmacological treatment is of paramount importance for treating severe psoriasis. Brodalumab, a monoclonal antibody against interleukin (IL) 17 receptor A, was granted marketing authorisation in the EU in 2017. The European Medicines Agency requested a postauthorisation safety study of brodalumab to address potential safety issues raised during drug development regarding major adverse cardiovascular events, suicidal conduct, cancer and serious infections.Methods and analysisBRodalumab Assessment of Hazards: A Multinational Safety is a multicentre observational safety study of brodalumab running from 2017 to 2029 using population-based healthcare databases from Denmark, Sweden, Norway, Netherlands, Germany and three different centres in Italy. A distributed database network approach is used, such that only aggregate data are exchanged between sites.Two types of designs are used: a case-time-control design to study acute effects of transient treatment and a variation of the new user active comparator design to study the effects of transient or chronic treatment. As comparators, inhibitors of TNF-α, inhibitors of IL-12 and IL-23, and other inhibitors of cytokine IL-17A are included.In the self-controlled case-time-control design, the risk of developing the outcome of interest during periods of brodalumab use is compared within individuals to the risk in periods without use.In the active comparator cohort design, new users of brodalumab are identified and matched to new users of active comparators. Potential baseline confounders are adjusted for by using propensity score modelling. For outcomes that potentially require large cumulative exposure, an adapted active comparator design has been developed.Ethics and disseminationThe study is approved by relevant authorities in Denmark, Norway, Sweden, the Netherlands, Germany and Italy in line with the relevant legislation at each site. Data confidentiality is secured by the distributed network approach. Results will be published in peer-reviewed journals.Trial registration numberEUPAS30280.

BackgroundCase reports of Guillain Barrè syndrome (GBS) following the Coronavirus Disease 2019 (COVID-19) vaccines administration have been reported. This study investigated the risk of GBS after vaccination with anti-COVID-19 vaccines (BNT162b2/Tozinameran; mRNA-1273/Elasomeran, ChAdOx1-S and Ad26.COV2-S) in the population aged ≥12 years in Italy.MethodsWe conducted a self-controlled case series study (SCCS) using national data on COVID-19 vaccination linked to emergency care/hospital discharge databases. The outcome was the first diagnosis of GBS between 27 December 2020 and 30 September 2021.Exposure risk period were days 0 (vaccination day) through 42 days following each of the 2 vaccine doses. The remaining periods were considered as non at risk (baseline) period.The SCCS model, adapted to event-dependent exposures, was fitted using unbiased estimating equations to estimate relative incidences (RIs) and excess of cases (EC) per 100,000 vaccinated by dose and vaccine product. Calendar period was included as time-varying confounder in the model.ResultsThe study included 15,986,009 persons who received at least one dose of Covid-19 vaccine. During the 42-day risk interval there were a total of 67 cases of GBS after the first dose and 41 cases after the second dose. In the 42-day risk interval, increased risks were observed after the administration of first dose (RI=6.83; 95% CI 2.14-21.85) and second dose (RI=7.41; 95% CI 2.35-23.38) for mRNA-1273 vaccine, corresponding to 0.4 and 0.3 EC per 100,000 vaccinated, respectively. Increased risk was also observed after the first dose of ChAdOx1-S vaccine (RI=6.52; 95% CI 2.88-14.77), corresponding to 1.0 EC per 100,000 vaccinated. There was no evidence of increased risk of GBS after vaccination with BNT162b2 and Ad26.COV2-S vaccines.In the subgroup analysis by sex an increased risk of GBS was observed among both males and females after mRNA-1273 vaccine. in males an increased risk was observed after the first dose, with a borderline significance (RI=5.26; 95% CI 0.94-29.42; p=0.06) and the second dose (RI=16.50; 95% CI 3.01-90.56) and in females after the first dose (RI=13.44; 95% CI 2.83-63.80). There was also evidence of an increased risk after a first dose of ChAdOx1-S in males (RI=4.94; 95% CI 1.84-13.28) and females (RI=7.14; 95% CI 1.94-26.19).In the subgroup analysis by age, there was evidence of an increased risk of GBS with mRNA-1273 vaccine among those aged ≥60 years after the first (RI=8.03; 95% CI 2.08-31.03) and second dose (RI=7.71; 95% CI 2.38-24.97). After a first dose of ChAdOx1-S there was evidence of an increased risk of GBS in those aged 40-59 (RI=4.50; 95% CI 1.37-14.79) and in those aged ≥60 years (RI=6.84; 95% CI 2.56-18.28). There was no evidence of increased risk of GBS after vaccination with BNT162b2 and Ad26.COV2-S vaccines in the subgroup analysis by age and sex.Study limitations include that the outcome was not validated through review of clinical records, the possibility of time-dependent residual confounding and the imprecision of the obtained estimates in the subgroup analysis due to the very low number of events.ConclusionsIt is important the continuous monitoring of the suspected adverse events of the COVID-19 vaccines as key component of any vaccination program. Results from this large SCCS study showed an increased risk of GBS after first and second dose of mRNA-1273 and first dose of ChAdOx1-S. However, these findings were compatible with a small number of EC. Our data are reassuring regarding BNT162b and Ad26.COV2-S vaccines with respect to GBS outcome. No increased risk of GBS was detected following each of BNT162b vaccine dose nor any increased risk after Ad26.COV2-S vaccine dose.

BackgroundIn immunosuppression after transplantation, several multi-drug approaches are used, involving calcineurin inhibitors (CNI: tacrolimus-TAC or cyclosporine-CsA), antimetabolites (antiMs), mammalian target of rapamycin inhibitors (mTORis), and corticosteroids. However, data on immunosuppressive therapy by organ and its space–time variability are lacking.MethodsAn Italian multicentre observational cohort study was conducted using health information systems. Patients with incident transplant during 2009–2019 and resident in four regions (Veneto, Lombardy, Lazio, and Sardinia) were enrolled. The post-transplant immunosuppressive regimen was evaluated by organ, region, and year.ResultsThe most dispensed regimen was triple-drug therapy for the kidneys [tacrolimus (TAC) + antiM + corticosteroids = 41.5%] and heart [cyclosporin + antiM + corticosteroids = 36.6%] and double-drug therapy for liver recipients (TAC + corticosteroids = 35.4%). Several differences between regions and years emerged with regard to agents and the number of drugs used.ConclusionA high heterogeneity in immunosuppressive therapy post-transplant was found. Further studies are needed in order to investigate the reasons for this variability and to evaluate the risk–benefit profile of treatment schemes adopted in clinical practice.

Objectives To ascertain if the use of hydroxychloroquine(HCQ)/cloroquine(CLQ) and other conventional DMARDs (cDMARDs) and rheumatic diseases per se may be associated with COVID-19-related risk of hospitalization and mortality. Methods This case–control study nested within a cohort of cDMARD users was conducted in the Lombardy, Veneto, Tuscany and Lazio regions and Reggio Emilia province. Claims databases were linked to COVID-19 surveillance registries. The risk of COVID-19-related outcomes was estimated using a multivariate conditional logistic regression analysis comparing HCQ/CLQ vs MTX, vs other cDMARDs and vs non-use of these drugs. The presence of rheumatic diseases vs their absence in a non-nested population was investigated. Results A total of 1275 patients hospitalized due to COVID-19 were matched to 12 734 controls. Compared with recent use of MTX, no association between HCQ/CLQ monotherapy and COVID-19 hospitalization [odds ratio (OR) 0.83 (95% CI 0.69, 1.00)] or mortality [OR 1.19 (95% CI 0.85, 1.67)] was observed. A lower risk was found when comparing HCQ/CLQ use with the concomitant use of other cDMARDs and glucocorticoids. HCQ/CLQ was not associated with COVID-19 hospitalization as compared with non-use. An increased risk for recent use of either MTX monotherapy [OR 1.19 (95% CI 1.05, 1.34)] or other cDMARDs [OR 1.21 (95% CI 1.08, 1.36)] vs non-use was found. Rheumatic diseases were not associated with COVID-19-related outcomes. Conclusion HCQ/CLQ use in rheumatic patients was not associated with a protective effect against COVID-19-related outcomes. The use of other cDMARDs was associated with an increased risk when compared with non-use and, if concomitantly used with glucocorticoids, also vs HCQ/CLQ, probably due to immunosuppressive action.

Purpose To analyse the drug use pattern in women with psoriasis before, during and after pregnancy. Methods All children born (2009-2016) in a central Italian region (Lazio) to mothers with a diagnosis of psoriasis were identified. Drug use patterns (biologicals, systemic, and topical), and discontinuation and switching of drug therapies before, during, and after pregnancy were studied. Findings were compared with data from a population exposed to similar drug therapies (eg, antirheumatic drugs). Results Among 3499 deliveries by women affected by psoriasis, 1876 (53.6%) were diagnosed with this condition before the Last Menstrual Period (LMP). Of these, 525 (27.9%) had at least one drug prescription for psoriasis therapy during 6 months before LMP. For each class of drugs considered, there was a general decrease in its use during pregnancy. Considering the two trimesters preceding LMP and the three trimesters of pregnancy, the following percentages of prescriptions were observed: from 10.5% to 0% for biologicals, 7.2% to 2.5% for the conventional systemic drugs, and 51.1% to 9.4% for the topical treatments. After delivery, previous treatments were resumed. Similar results were observed for rheumatoid arthritis, a chronic condition. Conclusions Majority of drugs come with warnings regarding potential embryo-fetotoxicity, which might play a role in the decision to continue treatments during pregnancy. According to our study pregnancy appears to have a significant influence on drug prescriptions of different pharmacological treatments for psoriasis.

Ensuring drug safety for pregnant women through prescription drug monitoring is essential. The aim of this study was to describe the prescription pattern of medicines among pregnant immigrant women from countries with high migratory pressure (HMPCs) compared to pregnant Italian women. The prevalence of drug prescriptions among the two study populations was analysed through record linkage procedures applied to the administrative databases of eight Italian regions, from 2016 to 2018. The overall prevalence of drug prescription was calculated considering all women who received at least one prescription during the study period. Immigrants had a lower prevalence of drug prescriptions before (51.0% vs. 58.6%) and after pregnancy (55.1% vs. 60. 3%). Conversely, during pregnancy, they obtained a slightly higher number of prescriptions (74.9% vs. 72.8%). The most prescribed class of drugs was the blood and haematopoietic organs category (category ATC B) (56.4% vs. 45.9%, immigrants compared to Italians), followed by antimicrobials (31.3% vs. 33.7%). Most prescriptions were appropriate, while folic acid administration 3 months before conception was low for both study groups (3.9% immigrants and 6.2% Italians). Progesterone seemingly was prescribed against early pregnancy loss, more frequently among Italians (16.5% vs. 8.1% immigrants). Few inappropriate medications were prescribed among antihypertensives, statins and anti-inflammatory drugs in both study groups.

ObjectivesTo investigate the association between SARS-CoV-2 mRNA vaccines, BNT162b2 and mRNA-1273, and myocarditis/pericarditis.DesignSelf-Controlled Case Series study (SCCS) using national data on COVID-19 vaccination and emergency care/hospital admissions.SettingItalian Regions (Lombardia, Friuli Venezia Giulia, Veneto, Lazio).Participants2,861,809 individuals, aged 12-39 years, vaccinated with the first doses of mRNA vaccines (2,405,759 BNT162b2 and 456,050 mRNA-1273) between 27 December 2020 and 30 September 2021.Main outcome measuresFirst diagnosis of myocarditis/pericarditis within the study period. The incidence of events in the exposure risk periods (0-21 days from the vaccination day, subdivided in three equal intervals) for first and second dose was compared with baseline period. The SCCS model was fitted using conditional Poisson regression to estimate Relative Incidences (RI) and Excess of Cases (EC) per 100,000 vaccinated by dose, age, gender and brand.ResultsDuring the study period, 441 participants aged 12-39 years developed myocarditis/pericarditis (346 BNT162b2 and 95 mRNA-1273). During the 21-day risk interval there were 114 cases of myocarditis/pericarditis (74 BNT162b2 and 40 mRNA-1273) corresponding to a RI of 1.27 (0.87-1.85) and 2.16 (1.50-3.10) after first and second dose, respectively.An increased risk of myocarditis/pericarditis at [0-7) days was observed after first [RI=6.55; 95% Confidence Interval (2.73-15.72); EC per 100,000 vaccinated=2.0 (1.5-2.3)] and second dose [RI=7.59 (3.26-17.65); EC=5.5 (4.4-5.9)] of mRNA-1273 and after second dose of BNT162b2 [RI=3.39 (2.02-5.68); EC=0.8 (0.6-1.0)]. In males, an increased risk at [0-7) days was observed after first [RI=12.28, 4.09-36.83; EC=3.8 (3.1-4.0)] and second dose [RI=11.91 (3.88-36.53); EC=8.8 (7.2-9.4)] of mRNA-1273 and after second dose of BNT162b2 [RI=3.45 (1.78-6.68); EC=1.0 (0.6-1.2)]. In females, an increased risk at [0-7) days was observed after second dose of BNT162b2 [RI=3.38 (1.47-7.74); EC=0.7 (0.3-0.9)]. At [0-7) days an increased risk following second dose of BNT162b2 was observed in the 12-17 years old [RI=5.74, (1.52-21.72); EC=1.7 (0.7-1.9)] and in 18-29 years old [RI=4.02 (1.81-8.91); EC=1.1 (0.6-1.3)]. At [0-7) days an increased risk after first [RI=7.58 (2.62-21.94); EC=3.5 (2.4-3.8)] and second [RI=9.58 (3.32-27.58); EC=8.3 (6.7-9.2)] dose of mRNA-1273 was found in 18-29 years old and after first dose in 30-39 years old [RI=6.57 (1.32-32.63); EC=1.0 (0.3-1.1)].ConclusionsThis population-based study indicates that mRNA vaccines were associated with myocarditis/pericarditis in the population younger than 40 years, whereas no association was observed in older subjects. The risk increased after the second dose and in the youngest for both vaccines, remained moderate following vaccination with BNT162b2, while was higher in males following vaccination with mRNA-1273. The public health implication of these findings should be weighed in the light of the overall efficacy and safety profile of both vaccines.

Background: Evidence-based recommendations for outpatient management of COVID-19 were published by the Italian Medicines Agency (AIFA) to limit the use of off-label treatments. The aim of this study is to measure the use of outpatient drug treatments in a COVID-19-positive population, taking into account the Italian regulatory agency’s advices.Methods: A descriptive observational study was conducted. All patients testing positive for COVID-19 residing in Lazio region, Italy, with diagnosis date between March 2020 and May 2021 were selected, and outpatient medicine prescription patterns were identified.Results: Independent of AIFA recommendations, the use of drug therapy in the management of outpatient COVID-19 cases was frequent (about one-third of the cases). The most used drug therapy was antibiotics, specifically azithromycin, despite the negative recommendation of AIFA, while the use of corticosteroids increased after the positive recommendation of regulatory agency for the use in subjects with severe COVID-19 disease. The use of hydroxychloroquine was limited to the early pandemic period where evidence on its potential benefit was controversial. Antithrombotics were widely used in outpatient settings, even if their use was recommended for hospitalized patients.Conclusion: In this study, we show a frequent use of drug therapy in the management of outpatient cases of COVID-19, mainly attributable to antibiotics use. Our research highlights the discrepancy between recommendations for care and clinical practice and the need for strategies to bridge gaps in evidence-informed decision-making.

Purpose Infertility is a topic of growing interest, and female infertility is often treated with gonadotropins. Evidence regarding comparative safety and efficacy of different gonadotropin formulations is available from clinical studies, while real-world data are missing. The present study aims to investigate effectiveness and safety of treatment with different gonadotropin formulations in women undergoing medically assisted procreation treatments in Latium, a region in central Italy, through a real-world data approach. Methods A retrospective population-based cohort study in women between the ages of 18 and 45 years who were prescribed with at least one gonadotropin between 2007 and 2019 was conducted. Women were enrolled from the regional drug dispense registry, and data on their clinical history, exposure to therapeutic cycles (based on recombinant “REC” or extractives “EXT” gonadotropin, or combined protocol “CMD” (REC + EXT)), and maternal/infantile outcomes were linked from the regional healthcare administrative databases. Multivariate logistic regression models were applied to estimate the association between exposure and outcomes. Results Overall, 90,292 therapeutic cycles prescribed to 35,899 women were linked to pregnancies. Overall, 15.8% of cycles successfully led to pregnancy. Compared to extractives, recombinant and combined treatments showed a stronger association with conception rate (RRREC adj = 1.06, 95% CI: 1.01–1.12; RRCBD adj = 1.17, 95% CI: 1.11–1.24). Maternal outcomes occurred in less than 5% of deliveries, and no significant differences between treatments were observed (REC vs EXT, pre-eclampsia: RR adj = 1.24, 95% CI: 0.86–1.79, ovarian hyperstimulation syndrome: RR adj = 1.25, 95% CI: 0.59–2.65, gestational diabetes: RR adj = 1.06, 95% CI: 0.84–1.35). Regarding infantile outcomes, similar results were obtained for different gonadotropin formulations (REC vs EXT: low birth weight: RR adj = 0.98, 95% CI: 0.83–1.26, multiple births: RR adj = 1.06, 95% CI: 0.92–1.23, preterm birth: RR adj = 1.03, 95% CI: 0.92–1.26). Conclusions Efficacy and safety profiles of REC proved to be similar to those of EXT. Regarding the efficacy in terms of conception rate and birth rate, protocols using the combined approach performed slightly better. Outcomes related to maternal and infantile safety were generally very rare, and safety features were overlapping between gonadotropin formulations.

Monitoring medicine prescriptions in pregnancy is an aspect of extreme interest in term of public health.A retrospective prevalence study using administrative healthcare databases was performed in order to evaluate medication prescriptions in Italy. A cohort of 274,938 pregnant women (15-49 years) residing in three Italian regions (Emilia-Romagna, Lazio, Puglia), who delivered in 2014-2017, were enrolled. The prevalence of medication use was estimated as the proportion of pregnant women with any medication prescription in each of the following five trimesters: 1 before pregnancy (pre-T), 3 during pregnancy (1st TP, 2nd TP, 3rd TP) and 1 after pregnancy (post-T).About 80% of enrolled pregnant women received at least one prescription during pregnancy, 36.5% before pregnancy and 50.7% in the post-partum. The most prescribed medicine was folic acid (42%), mostly used in 1st TP (35%). Progesterone use was concentrated in 1st TP (19%) and increased as the number of previous abortions. Pregnancy use of antidiabetics, antihypertensives, and thyroid preparations were 24.1‰, 21.5‰, 101.8‰, respectively.At the national level, this study confirmed the prescriptive trend observed in other European studies, but a regional variability for all medication groups was found. Further studies are needed in order to identify determinants of medication prescriptions during pregnancy in Italy.

To investigate the association of the 2019–2020 influenza vaccine with prognosis of patients positive for SARS-CoV-2A, a large multi-database cohort study was conducted in four Italian regions (i.e., Lazio, Lombardy, Veneto, and Tuscany) and the Reggio Emilia province (Emilia-Romagna). More than 21 million adults were residing in the study area (42% of the population). We included 115,945 COVID-19 cases diagnosed during the first wave of the pandemic (February–May, 2020), 34.6% of these had been vaccinated against influenza. Three outcomes were considered: hospitalization, death, and intensive care unit (ICU) admission/death. The adjusted relative risk (RR) of being hospitalized in the vaccinated group when compared with the non-vaccinated group was 0.87 (95% CI: 0.86–0.88). This reduction in risk was not confirmed for death (RR = 1.04, 95% CI: 1.01–1.06), or for the combined outcome of ICU admission or death. In conclusion, our study, conducted on the vast majority of the population during the first wave of the pandemic in Italy, showed a 13% statistically significant reduction in the risk of hospitalization in some geographical areas and in the younger population. No impact of seasonal influenza vaccination on COVID-19 prognosis in terms of death and death or ICU admission was estimated.

to describe and compare the effectiveness of national and local lockdowns in controlling the spread of COVID-19.a rapid review of published and grey literature on COVID-19 pandemic was conducted following predefined eligibility criteria by searching electronic databases, repositories of pre-print articles, websites and databases of international health, and research related institutions and organisations.of 584 initially identified records up to 5 July 2020, 19 articles met the inclusion criteria and were included in the review. Most of the studies (No. 11) used the reproduction number (Rt) as a measure of effect and in all of them areduction of the estimated value at post-intervention period was found. The implementation of lockdown in 11 European countries was associated with an average 82% reduction of Rt, ranging from a posterior Rt of 0.44 (95%CI 0.26-0.61) for Norway to a posterior Rt of 0.82 (95%CI 0.73- 0.93) for Belgium. Changes in infection rates and transmission rates were estimated in 8 studies. Daily changes in infection rates ranged from -0.6% (Sweden) to -11.3% (Hubei and Guangdong provinces). Additionally, other studies reported a change in the trend of hospitalizations (Italy, Spain) and positive effects on the doubling time of cases (Hubei, China) after lockdown.results of this rapid review suggest a positive effect of the containment measures on the spread of COVID-19 pandemic, with a major effect in countries where lockdown started early and was more restrictive. Rigorous research is warranted to evaluate which approach is the most effective in each stage of the epidemic and in specific social contexts, in particular addressing if these approaches should be implemented on the whole population or target specific risk groups.

Background Gonadotropins (Gonas) are hormones that play a central role in the follicular growth of women but also useful in male infertility. Gonas used for infertility treatment in women are available as urinary extracts or recombinants. In 2015, the first biosimilar of follitropin alfa was authorised. Objectives We aimed to evaluate use patterns, temporal and spatial variations of Gonas biosimilar formulations in an central Italian region. Methods From administrative healthcare databases of Lazio region, we extracted prescriptions that have occurred over the years 2015-2019. Gona's use was grouped as treatment with urinary (u) and recombinant (r). Special focus was made on biosimilar r-Gona. Use patterns were investigated with respect to characteristics of the patients treated, time trends, differences among local health units and type of prescribing physician. Results For the study period, we retrieved 136,333 Gona dispensations for 22,325 patients. The 10,927 r-Gona biosimilar dispensations (8.01% of all claims, of which 99.43% Bemfola®, and 0.57% Ovaleap®), were mostly referred to women, aged 18-45 years, (87.11% of all patients). Median age was 37 years for women, 38 for men. Since its authorisation, biosimilar r-Gona steadily gained market from 2015 (0,4% of claims) to 2017 (22,7%) followed by a decrease in 2019 (4,3%). Biosimilars claims are more frequent in treating men (10,8%) than women (6,1%). Most biosimilar prescriptions were issued by general practitioners (86.4%), followed by specialists (10.2%) and others. Biosimilar use patterns varied between different local health units (IQR 3.2%-8,5%). Conclusions In clinical pratice, r-Gona biosimilar dispensation, 8,8% of Gonas. are mostly prescribed from general practitioners and are proportionately more targeted at men than women. Further investigation is needed. Key messages More and more men and women are using artificial insemination techniques; it is important to monitor fertility drug use patterns. In times of savings for the economic system,the use of the biosimilar drugs is of increasing interest.

Background Gonadotropins (Gona) are commonly used for infertility treatment in women. They are available as urinary purified extracts (u-Gona) and recombinants (r-Gona). Objectives:We investigated if socio-demographic characteristics of treated women, year of dispensation and type of prescriber may play a role in the choice of a treatment with respect to the other. Methods From administrative healthcare databases, we collected claims of Gona for women, aged 18-45, enrolled in the health care system in the year preceding the first prescription (years 2009-2018). Treatment cycles were defined as a 21-day mobile time window. We identified three groups: u-Gona, r-Gona and treatment with both formulations (m-Gona). To identify determinants, we linked women with the socio-economic position (SEP), a composite deprivation index, based on the 2011 Italian Census data,categorized in 4 levels (high, medium-high, medium-low, low). We associated prescriptions with the type of prescriber, distinguishing between specialists and general practitioners. Results We retrieved 38,598 Gona treatment cycles prescribed to 23,412 women and distributed between formulations as follows: r-Gona 47.4%, u-Gona 26.3% and m-Gona 26.3%. The median age was 38 years for r-Gona and u-Gona, 39 for m-Gona. Comparing the type of prescriber, specialists were more likely to prescribe u-Gona instead of r-Gona (OR: 2.14; 95%CI: 2.02-2.27) than general practitioners. No relation was found between SEP and Gona formulations, except for patients with the highest level who were more likely to be prescribed with r-Gona instead of u-Gona (OR: 1.12; 95%CI: 1.03-1.21). Time trends showed that treatment choices changed over time. Conclusions In the Lazio region, the choice of gonadotropin formulations varied over time and was found to be related to the prescriber and partly to socio-economic position. An analysis of outcomes related to different treatments is under way. Key messages More and more women are using artificial insemination techniques; it is important to monitor fertility drug use patterns and determinants of the choice of a treatment. The use of fertility drugs is a multifactorial phenomenon and a matter of public health interest.

Guidelines for the treatment of rheumatoid arthritis (RA) recommend the use of conventional synthetic disease modifying anti-rheumatic drugs (cs-DMARDs) at the onset of the disease and only in the case of therapeutic failure, the addition of a biological drug (b-DMARD) is suggested. The study aimed to evaluate determinants for first-line biological treatment in patients with RA in clinical practice. A cohort of patients with RA, resident in Lazio, a central Italian Region, where Rome is located, and with at least one disease modifying anti-rheumatic drugs (DMARD) prescription between 2010 and 2016 was selected using health information systems linkable with each other by an individual unique anonymous identifier. In particular RA cohort was defined retrieving all patients with at least a RA disease code in regional data claims (hospital discharge, exemption code, emergency department access, or therapeutic plan). Only new users were included and the first-line treatment was identified: cs-DMARD or b-DMARD. Descriptive analysis according to type of DMARD treatment was performed. Through multivariate logistic regression models (odds ratio [OR]; confidence interval [CI95%]) determinants of therapy such as age, comorbidity, and comedication were investigated. Finally, switching during the first year of treatment from cs-DAMARDs to b-DMARDs was analyzed. DMARD-new users with RA were 5641; 7.1% of them with b-DMARD as first-line treatment. Considering the year of dispensing, this percentage ranged from 4.9% (2011) to 8.2% (2015). Among cs-DMARD the most prescribed active agent was methotrexate (59.3%), while among b-DMARD it was etarnecept (37.0%), followed by adalimumab (21.2%). The average age of the cohort was 54 years with 77% of women. Determinants of first-line b-DMARD use were: age (OR65 = 3.7; 2.6–5.2, OR[30–45)vs>65 = 1.7; 1.2–2.4, OR[45–55)vs>65 = 1.6; 1.1–2.4, OR[55–65)vs>65 = 1.2; 0.8–1.7), cancers (OR = 2.3; 1.3–4.2), cardio-cerebrovascular disease (OR = 1.4; 1.0–1.9), use of non-steroidal anti-inflammatory drugs (NSAIDs) (OR = 0.6; 0.4–0.7) and corticosteroids (OR = 0.6; 0.5–0.7) in the 6 months preceding diagnosis. In the first year of treatment, we observed a percentage of switch from cs-DMARDs to b-DMARDs of 7.9%. In clinical practice, about 7% of patients with RA are prescribed with a b-DMARD as first-line treatment. This therapeutic option, even if not supported by guide lines, is mostly link to younger age and clinical profile of the patients.

The availability of subcutaneous (SC) and intravenous (EV) formulations of trastuzumab and the recent release of the biosimilar EV version (10/2018) increase the offer for the treatment of patients with breast or gastric cancer HER2 positive. In this context, it is necessary to build therapeutic scenarios form avalible data in order to estimate the potential savings for the Regional Health Service (RHS) taking into account the appropriateness of use and patient's preferences.To evaluate the available comparative evidence regarding the effectiveness and safety of the different trastuzumab formulations; to analyze the supply of trastuzumab by type of administration (EV/SC) in Lazio in 2018, identifying the most appropriate use; to hypothesize a cost-effective scenario for the Regional Health Service (SSR) in 2019. Mehods. With the working group formed by clinicians and methodologists, we analysed the evidence of efficacy and safety available to date for the different formulations of trastuzumab, also taking into account the recent availability of biosimilars and with particular regard to the phenomenon of the potential switch between different therapeutic options. In addition, for the year 2019 the available economic impact assessments were also simulated with data from the Lazio Region. Through the datas from direct pharmaceutical products, the transtuzumab cycles supplied in 2018 were identified separately for the available formulations (EV/SC). For each cycle of therapy, starting from the date of delivery, the possible presence of a concomitant treatment (± 2 days) was investigated, tracing the type and method of administration. The treatments (concomitant with trastuzumab) were identified for which there were conflicting modes of administration. In addition, the supply of SC per dispensing structure was evaluated and, on the basis of this information, a scenario of use was hypothesized that takes into account costs and plausible consumption.A review of the literature summarized the available evidence on the efficacy and safety of the use of trastuzumab in the recorded therapeutic indications. The review was discussed with the working group and used to reproduce, at regional level, the estimates of the economic impact of the different therapeutic choices possible with trastuzumab. As regards the data on the use of trastuzumab, in the Lazio Region in 2018, 22,214 treatment cycles were observed (at a cost of 33 million euro) for 2,407 patients; new users accounted for 52.2%. 46.8% of the cycles were administered via SC; the use of the biosimilar was observed from October onwards and involved 143 cycles (0.6%). In 68.4% of the cycles trastuzumab was administered in monotherapy; among the therapies associated with trastuzumab, the most frequent was pertuzumab (n=4,258, 19.2% of the total cycles), followed by paclitaxel (n=1,364, 6.1% of the total cycles). Among the cycles of trastuzumab in concomitant therapy (N=7,022), 17.3% was administered via SC despite the presence of other drugs administered via EV. The prescriptive pattern of trastuzumab was heterogeneous for the different delivery structures. The SC administration presents a variability in the supply from 26% to 70% (interquartile range) and does not seem to be related to the type and volume of activity of the hospital. If the biosimilar EV is expected to account for 55% of consumption by 2019, thus reducing the use of the EV originator to 10% and the SC originator to 35%, savings of more than €7 million.Through the use data of the different formulations available for trastuzumab and taking into account the prescriptive appropriateness (and patient preferences), it has been possible to identify a SSR scenario of economic convenience due to the greater use of the biosimilar.

Purpose Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma often refractory to currently available treatments (immuno-chemotherapy/autologous-stem-cell-transplantation-ASCT). Recently, new cell therapies have been approved for patients failing two conventional treatments, CAR-T (Chimeric-Antigen-Receptor-T-cell), committing payers in planning and implementing their use. We aim to define, using Real World Data (RWD), a reproducible procedure that allows identification of CAR-T target population for DLBCL. Methods Through the linking of electronic healthcare datasets (EHD), we identified patients with non-Hodgkin's Lymphoma (NHL), resident in Lazio region (2010-2015), aged ≥20 years. DLBCL patients were followed using pathological anatomy (PA) reports, up to 3 years. To be defined as relapsed after two treatment lines, patients must have had new chemotherapy and/or NHL hospitalization after ASCT or at the end of the second chemotherapy. The incident rate of second relapse (R2-rate) was extended to the population without PA reports. Result NHL incident patients were 7384, 68% presented a PA report and, 29% of these had DLBCL codes. Patients who relapsed after two treatment lines were 47 (39%) in the subgroup of patients who received ASCT and 138 (41%) in that with second chemotherapy treatment. Patients in the two subgroups were very different in terms of age and comorbidity. The annual incident number of DLBCL was estimated to be 329 which multiplied by R2-rate (13.7%) gives 45 patients per year eligible for CAR-T. Discussion This study shows how RWD allows the identification of a target population with new advanced therapies. This approach is rigorous, transparent and verifiable over time.

BACKGROUND The final days of life of Brain Tumor patients (BT) present special challenges and often palliative care approach is underutilyzed. Several studies reported that BT patients in the last months of life receive frequent hospital readmissions and ER accesses as result of bad quality of End of Life care. Early integration of pallative care has been demonstrated to improve quality of care in advanced stage of disease and quality of death in cancer patients. With the aim to evaluate pattern of treatment and the rate of hospital readmission in the last months of life, we retrospectively analyzed a consecutive serie of BT patients discharged after a diagnosis of BT. MATERIAL AND METHODS Data regarding hospital readmission and treatment received in the last two months of life were collected from the Lazio Region Healthcare database. Adult patients discharged with diagnosis ICD-9 191.* between 1/1/2010 until 31/12/2019, were included in this study. RESULTS 6672 patients were identified and 3045 who have died before 31/12/2019 were included (median age 67 y;M1700). In the last two month of life 42.6% received hospital reamission (4.6% intensive care unit) and 37.9% had ER accesses. 24.5% received chemotherapy and 12.1% radiotherapy. In the last 30 days 33% were readmitted in hospital and 24.2% were admitted in ER. 11.7% were treated with chemotherapy and 6% with radiotherapy. CONCLUSION Strategies to improve quality of care at the end of life and to decrease re-hospitalization and futile treatments are becoming increasingly important to improve quality of death and to reduce costs of Healthcare System.

In Italy, direct oral anticoagulant drugs (DOACs) were authorized for stroke prevention in patients with non-valvular atrial fibrillation (NVAF) in 2013. There is conflicting evidence on their benefit-risk profile under real world conditions.The Italian Medicines Agency funded this study to investigate effectiveness and safety of DOACs compared to vitamin K antagonists (VKAs) in three Italian regions. An observational study was conducted with a sequential propensity-score-matched new user parallel-cohort design in the period July 2013-December 2015 using administrative health data. DOAC users with NVAF diagnosis were 1:1 matched to VKA users based on a PS which accounted for over 90 potential confounders at baseline. Applying an as-treated approach with a 90-day renewal grace time, patients were followed from the day after the first prescription of the study drug until occurrence of the outcome, death, discontinuation, switch, end of health plan enrolment, or study end. Outcomes were total and cardiovascular mortality, acute myocardial infarction, ischemic and haemorrhagic stroke, and gastrointestinal bleeding. Analyses were performed, using Cox proportional hazard models stratified by matched set. The results of the regional analyses were combined through a random-effects meta-analysis.During the first 30 months of authorisation for NVAF, DOACs were increasingly prescribed. Overall, 72,434 new anticoagulant users were enrolled, 34% of whom received a DOAC. After PS matching, 37,266 patients contributed to the analysis. No differences between the study groups were found for total and cardiovascular mortality, myocardial infarction and ischemic stroke. DOAC users were at higher risk of gastrointestinal bleeding (HR 1.41, 95%CI 1.07-1.86) and at a not significant lower risk of haemorrhagic stroke (HR 0.36, 95%CI 0.10-1.33).The present study confirms findings from previous research regarding bleeding events, whereas we did not find a reduced risk of mortality in DOAC users. Further research on single active agents and specific populations is warranted.

BackgroundThe relationship between guideline adherence and outcomes in patients with acute myocardial infarction (AMI) has been widely investigated considering the emergency, acute, post-acute phases separately, but the effectiveness of the whole care process is not known.AimThe study aim was to evaluate the effect of the multicomponent continuum of care on 1-year survival after AMI.MethodsWe conducted a cohort study selecting all incident cases of AMI from health information systems during 2011-2014 in the Lazio region. Patients' clinical history was defined by retrieving previous hospitalizations and drugs prescriptions. For each subject the probability to reach the hospital and the conditional probabilities to survive to 30 days from admission and to 31-365 days post discharge were estimated through multivariate logistic models. The 1-year survival probability was calculated as the product of the three probabilities. Quality of care indicators were identified in terms of emergency timeliness (time between residence and the nearest hospital), hospital performance in treatment of acute phase (number/timeliness of PCI on STEMI) and drug therapy in post-acute phase (number of drugs among antiplatelet, β-blockers, ACE inhibitors/ARBs, statins). The 1-year survival Probability Ratio (PR) and its Bootstrap Confidence Intervals (BCI) between who were exposed to the highest level of quality of care (timelinessResultsWe identified 38,517 incident cases of AMI. The out-of-hospital mortality was 27.6%. Among the people arrived in hospital, 42.9% had a hospitalization for STEMI with 11.1% of mortality in acute phase and 5.4% in post-acute phase. For a mean-severity patient the PR was 1.19 (BCI 1.14-1.24). The ratio did not change by gender, while it moved from 1.06 (BCI 1.05-1.08) for age85 years. For patients with diabetes and COPD a slight increase in PRs was also observed.ConclusionsThe 1-year survival probability post AMI depends strongly on the quality of the whole multicomponent continuum of care. Improving the performance in the different phases, taking into account the relationship among these, can lead to considerable saving of lives, in particular for the elderly and for subjects with chronic diseases.

Importance: Since the beginning of the Coronavirus Disease-19 (COVID-19) pandemic, Severe Acute Respiratory Syndrome-CoV-2 (SARS-CoV-2) infection has been a serious challenge for immune-compromised patients with immune-mediated inflammatory diseases (IMIDs). Objective: Our aim was to investigate the impact of COVID-19 in terms of risks of infection, hospitalization and mortality in a cohort of patients with rheumatoid arthritis (RA), psoriasis (PSO) or inflammatory bowel disease (IBD). Furthermore, we studied the impact of SARS-CoV-2 infection on the prescribed drug regimen in these patients. Methods: Through the record linkage between health information systems, a cohort of patients, ≥18 years old, assisted in the Lazio region and who had suffered from immune-mediated inflammatory diseases (RA, PSO, IBD) between 2007 and 2019, was identified. The risk of infection, hospitalization or mortality for COVID-19, was assessed by logistic regression models, and reported in an Odds Ratio (ORs; CI 95%), adjusting for sex, age and the Charlson Comorbidity Index. We also estimated these risks separately by IMID and in the subgroup of prevalent biologic drug users. We investigated deferral of biological treatments in the study population by comparing the prevalence of weekly use of biologicals (2019–2020) before and during the pandemic periods. Findings: Within the 65,230 patients with IMIDs, the cumulative incidence for COVID-19 was 303/10,000 ab. In this cohort of patients, we observed a significantly higher risk of SARS-CoV-2 infection than the general population: OR = 1.17 (95% CI 1.12–1.22). The risk was higher even considering separately each disease and in the subgroup of prevalent biologic drug users. This last subgroup of patients showed a higher risk of death related to COVID-19 (OR 1.89; 95% CI 1.04–3.33) than the general population. However, no differences in terms of risks of hospitalization or death related to COVID-19 were recorded in patients with the IMIDs. Comparing the 2019–2020 prevalence of weekly biological drug treatments in prevalent biologic drug users, we found a decrease (−19.6%) during the lockdown, probably due to pandemic restrictions. Conclusions and Relevance: Patients with IMIDs seem to have a higher risk of SARS-CoV2 infection. However, other than for patients with prevalent biologic drug treatment, no significant differences in terms of hospitalization and mortality were reported compared to the general populations; further investigation is warranted on account of unmeasured confounding. In addition, during the lockdown period, the COVID-19 emergency highlighted a lower use of biologic drugs; this phenomenon requires strict pharmacological monitoring as it could be a proxy of forthcoming long-term clinical progression.

In Italy, reimbursement restrictions regarding palivizumab prophylaxis approved in 2016 have been revoked in 2017, restoring use in infants with Gestational Age (GA) >29 weeks. Respiratory Syncytial Virus (RSV) hospitalisations and prevalence of palivizumab use in infants aged

Combined inhaled therapy in chronic obstructive pulmonary disease (COPD) is commonly used, but its benefits remain controversial. We assessed the effect of tiotropium in reducing COPD exacerbations when combined with long-acting β2 agonists (LABA) and/or inhaled corticosteroids (ICS). This new-user cohort study is based on administrative data from 3 Italian regions. We identified adults hospitalized for COPD from 2006 to 2009 who were newly prescribed a fixed LABA/ICS combination (double therapy). We classified patients according to whether tiotropium was also prescribed (triple therapy), using both intention-to-treat and as-treated approaches, and followed them for 1 year. COPD exacerbations were measured as outcomes. Multivariate and propensity score-adjusted hazard ratios (HRs, 95%CI) were calculated with Cox regression models. We identified 5717 new users of LABA/ICS of which 31.9% initiated triple therapy. In the intention-to-treat analysis, the multivariate adjusted HR for moderate, severe, and any exacerbations were 1.02 (95%CI 0.89-1.16), 0.92 (95%CI 0.76-1.12), and 1.08 (95%CI 0.91-1.28), respectively. The propensity score adjustment produced similar results. In the subcohort of patients with previous exacerbations, triple therapy was significantly associated with reduced risk of moderate exacerbations, compared to double therapy (HR 0.68, 95%CI 0.48-0.98 in intention-to-treat approach). In conclusion, the addition of tiotropium to LABA/ICS did not reduce COPD exacerbations compared to LABA/ICS alone. A protective role for moderate exacerbations was found in patients at risk of frequent exacerbations. Given the impact of exacerbations on health status and prognosis, it is crucial to target COPD patients for optimal treatment.

Purpose Whether inhaled medications improve long-term survival in Chronic Obstructive Pulmonary Disease (COPD) is an open question. The purpose of this study is to assess the impact of adherence to inhaled drug use on 5-year survival in COPD. Methods A population-based cohort study in three Italian regions was conducted using healthcare linked datasets (hospitalization, mortality, drugs). Individuals (45+ years) discharged after COPD exacerbation in 2006–2009 were enrolled. Inhaled drug daily use during 5-year follow-up was determined through Proportion of Days Covered on the basis of Defined Daily Doses. Five levels of time-dependent exposure were identified: (i) long-acting β2 agonists and inhaled corticosteroids (LB/ICS) regular use; (ii) LB/ICS occasional use; (iii) LB regular use; (iv) LB occasional use; and (v) respiratory drugs other than LB. Cox regression models adjusted for baseline (socio-demographic, comorbidities, drug use) and time-dependent characteristics (COPD exacerbations, cardiovascular hospitalizations, cardiovascular therapy) were performed. Results A total of 12 124 individuals were studied, 46% women, mean age 73,8 years. Average follow-up time 2,4 year. A total of 3415 subjects died (mortality rate = 11.9 per 100 person years). In comparison to LB/ICS regular use, higher risks of death for all remaining treatments were found, the highest risk for respiratory drugs other than LB category (HR = 1.63, 95%CI 1.43–1.87). Patients with regular LB use had higher survival than those with LB/ICS occasional use (HR = 0.89, 95%CI 0.79–0.99). Conclusions These findings support clinical guidelines and recommendations for the regular use of inhaled drugs to improve health status and prognosis among moderate–severe COPD patients. © 2016 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.