Acute treatment of migraine: quantifying the unmet need through real-world data in Italy.

OBJECTIVE: This study is describing subjects with migraine interrupting or not receiving triptans for acute treatment and providing a national-level estimate of people who might benefit from different therapeutic approaches. METHODS: This is a retrospective analysis using IQVIA Longitudinal Patient Database. Starting from 18 + years old individuals with migraine, we selected two cohorts: subjects with triptans prescriptions before and no triptans prescriptions after Index Date (triptan withdraw) and subjects without triptans prescriptions both before and after Index Date (no triptan prescriptions). Index Date was the first record of a health encounter for migraine in 2019. Individuals with cardiovascular disease (CVD) within no triptan prescriptions group were also quantified. RESULTS: Triptan withdraw and no triptan prescriptions cohorts numbered 605 and 3270, respectively, 5% and 29% of subjects with migraine. Mean age was 47 and 51 years respectively; women were more represented (~ 80%). Hypertension and thyroid disease were most frequent comorbidities; non-steroidal anti-inflammatory drugs were among most frequently recorded treatments. Subjects with CVD within no triptan prescriptions cohort were 621 and with triptan withdraw cohort subjects represented the basis to estimate those who might benefit from alternative options for the acute treatment of migraine, who were around 60,000 and accounted for 11% of subjects seeking primary care due to migraine. CONCLUSIONS: This analysis provides a real-word estimate of Italian people that might benefit from different therapeutic approaches as an alternative to triptans, which sometimes might be not effective and/or poorly tolerated. Such estimate should be intended as the lower limit of a wider range due to strict criteria adopted.

Factors associated with sick leave duration in patients suffering from major depressive disorder initiating antidepressant treatment: a real-world evidence study in Germany and Spain.

OBJECTIVE: To describe MDD patients starting antidepressant (AD) treatment by pharmacological approach and identify factors associated with a longer sick leave (SL) duration. METHODS: Retrospective study on IQVIA German Disease Analyser (specialists) and Spanish Longitudinal Patient Database (general practitioners and specialists). MDD patients initiating AD treatment between July 2016-June 2018 were grouped by therapeutic approach (AD monotherapy vs. combination/switch/add-on) and their characteristics were analysed descriptively. Multiple logistic regression models were run to evaluate factors affecting SL duration (i.e., >30 days). RESULTS: One thousand six hundred and eighty-five patients (monotherapy: 58%; combination/switch/add-on: 42%) met inclusion criteria for Germany, and 1817 for Spain (monotherapy: 83%; combination/switch/add-on: 17%). AD treatment influenced SL duration: combination/switch/add-on patients had a 2-fold and a 4-fold risk of having >30 days of SL than monotherapy patients, respectively in Germany and Spain. Patients with a gap of time between MDD diagnosis and AD treatment initiation had a higher likelihood of experiencing a longer SL both in Germany and Spain (38% higher likelihood and 6-fold risk of having >30 days of SL, respectively). CONCLUSIONS: A careful and timely selection of AD treatment approach at the time of MDD diagnosis may improve functional recovery and help to reduce SL, minimising the socio-economic burden of the disease.Key pointsThe major depressive disorder has a substantial impact on work absenteeism.The present study aimed to describe MDD patients starting antidepressant (AD) treatment depending on the pharmacological approach and to identify factors associated with longer sick leave (SL) duration.Patients receiving AD monotherapy had a lower likelihood of having more than 30 days of sick leave than those receiving AD combination/switch/add-on.Patients for whom a gap of time between MDD diagnosis and initiation of AD treatment was observed, showed a higher likelihood of having more than 30 days of sick leave.Because findings from this analysis relied on secondary data, the authors would like to claim the urgency of conducting prospective observational studies that further investigate the effect that different AD therapeutic approaches and timely initiation of treatment might exert on patients' recovery.

An Italian individual-level data study investigating on the association between air pollution exposure and Covid-19 severity in primary-care setting.

BACKGROUND: Several studies have been focusing on the potential role of atmospheric pollutants in the diffusion and impact on health of Covid-19. This study's objective was to estimate the association between ≤10 µm diameter particulate matter (PM10) exposure and the likelihood of experiencing pneumonia due to Covid-19 using individual-level data in Italy. METHODS: Information on Covid-19 patients was retrieved from the Italian IQVIA® Longitudinal Patient Database (LPD), a computerized network of general practitioners (GPs) including anonymous data on patients' consultations and treatments. All patients with a Covid-19 diagnosis during March 18th, 2020 - June 30th, 2020 were included in the study. The date of first Covid-19 registration was the starting point of the 3-month follow-up (Index Date). Patients were classified based on Covid-19-related pneumonia registrations on the Index date and/or during follow-up presence/absence. Each patient was assigned individual exposure by calculating average PM10 during the 30-day period preceding the Index Date, and according to GP's office province. A multiple generalized linear mixed model, mixed-effects logistic regression, was used to assess the association between PM10 exposure tertiles and the likelihood of experiencing pneumonia. RESULTS: Among 6483 Covid-19 patients included, 1079 (16.6%) had a diagnosis of pneumonia. Pneumonia patients were older, more frequently men, more health-impaired, and had a higher individual-level exposure to PM10 during the month preceding Covid-19 diagnosis. The mixed-effects model showed that patients whose PM10 exposure level fell in the second tertile had a 30% higher likelihood of having pneumonia than that of first tertile patients, and the risk for those who were in the third tertile was almost doubled. CONCLUSION: The consistent findings toward a positive association between PM10 levels and the likelihood of experiencing pneumonia due to Covid-19 make the implementation of new strategies to reduce air pollution more and more urgent.

Predictors of sick leave days in patients affected by major depressive disorder receiving antidepressant treatment in general practice setting in Germany.

OBJECTIVE: To identify sick leave days (SLD) predictors after starting antidepressant (AD) treatment in patients affected by major depressive disorder (MDD), managed by general practitioners, with a focus on different AD therapeutic approaches. METHODS: Retrospective study on German IQVIA® Disease Analyser database. 19-64 year old MDD patients initiating AD treatment between July-2016 and June-2018 were grouped by therapeutic approach (AD monotherapy versus combination/switch/add-on). Data were analysed descriptively by AD therapeutic approach, while a zero-inflated Poisson (ZIP) multiple regression model was run to evaluate SLD predictors. RESULTS: 8,891 patients met inclusion criteria (monotherapy: 66%; combination/switch/add-on: 34%). All covariates had an influence on SLD after AD treatment initiation. Focussing on variables that physicians may more easily intervene to improve outcomes, it was found that the expected SLD number of combination/switch/add-on patients was 1.6 times that of monotherapy patients, and the expected SLD number of patients diagnosed with MDD before the decision to start AD treatment was 1.2 times that of patients not diagnosed with MDD. CONCLUSIONS: A patient tailored approach in the selection of AD treatment at the time of MDD diagnosis may improve functional recovery and help to reduce the socio-economic burden of the disease.KEY POINTSFew studies previously investigated the effect of antidepressant treatment approaches on sick leave days in major depressive disorder.To the authors' knowledge, this is the first study evaluating the effect of different antidepressant treatment approaches on sick leave days in major depressive disorder in German patients.Patients receiving antidepressant monotherapy treatment seemed to lose fewer working days than patients receiving antidepressants combination/switch/add-on therapy, both before and after starting treatment, even if differences were more pronounced after treatment has started.The use of antidepressant monotherapy or combination/switch/add-on therapy was the strongest predictor of sick leave days after starting antidepressant treatment: the expected number of sick leave days for the combination/switch/add-on group was 1.6 times that of the monotherapy group.Among factors associated with increased sick leave days, antidepressant therapeutic approach and the promptness of starting the antidepressant treatment when major depressive disorder is diagnosed, are those on which physicians may more easily intervene to improve outcomes.Findings from the present study suggest that a patient tailored approach may improve functional recovery and help reducing the socio-economic burden of the disease.

Predictors of iron-deficiency anemia in primary care older adults: a real-world European multi-country longitudinal study.

BACKGROUND: Iron deficiency is a major cause of anemia in older people. Increasing the knowledge on the predictors of iron-deficiency anemia (IDA) may facilitate its timely diagnosis. AIM: To investigate the predictors of IDA in older people in four European countries. DESIGN AND SETTING: Retrospective longitudinal study. Primary care patients aged 65 or older (N = 24,051) in four European countries. METHODS: IDA predictors were estimated using multivariate Cox regression based on information gathered from national primary care databases: Italy (years 2002-2013), Belgium, Germany and Spain (years 2007-2012). Adjusted hazard ratios (aHR) with 95% confidence intervals (CIs) were estimated. RESULTS: In Spain and Belgium, men were at greater risk of IDA than women, while they had a lower risk in Italy. Weakness, irritability, alopecia and xerostomia were signs and symptoms significantly associated with IDA. Concurrent diseases, potential causes of anemia, positively associated with IDA were small bowel polyposis, stomach cancer, obesity, gastritis and peptic ulcer, esophagitis, Crohn's disease, celiac disease, lymphangiectasis, gastrectomy or gastric atrophy, gut resection or bypass, and cardiac prosthetic valve. Aspirin users had a 12-35% higher hazard of IDA than non-users. Similarly, corticosteroids and anti-acids were positively associated with IDA. A higher level of comorbidity was associated with an increased hazard of IDA in all countries. CONCLUSIONS: Specific signs and symptoms, chronic conditions, a greater comorbidity burden, and specific pharmacological treatments registered in primary care databases represent relevant predictors and correlates of incident IDA in older people in Europe. General practitioners might employ this information to obtain early diagnosis of IDA in community-dwelling older adults.

Gender differences in determinants of iron-deficiency anemia: a population-based study conducted in four European countries.

Iron-deficiency anemia (IDA) was the main condition contributing to higher rates of years lived with disabilities in women in 2016. To date, few studies have investigated gender differences in determinants of IDA in Europe. The aim of the present study was to evaluate the determinants of IDA among females and males in four European countries. IDA determinants were estimated using multivariable Cox regression based on information gathered from national primary care databases, namely Italy (for years 2002-2013), Belgium, Germany, and Spain (for years 2007-2012). Adjusted hazard ratios (aHR) with 95% confidence intervals (CIs) were estimated. Age was significantly associated with IDA in females of childbearing age in all four countries, as well as pregnancy, for which the aHR ranged from 1.20 (95% CI 1.15-1.25) in Italy to 1.88 (95% CI 1.53-2.31) in Germany. In males, the aHR increased with age starting from the 65-69 age group. Menometrorrhagia was associated with IDA in Germany (aHR 2.71, 95% CI 1.96-3.73), Italy (aHR 1.80, 95% CI 1.60-2.03), and Spain (aHR 1.52, 95% CI 1.31-1.76). A greater risk for women with alopecia was also observed. Weakness and headache indicated a higher risk in both men and women. Patients with diseases characterized by blood loss or gastrointestinal malabsorption were also at significantly increased risk. Physicians should encourage women of childbearing age to adhere to dietary recommendations regarding iron intake and regularly prescribe screening of iron status. Upper and lower gastrointestinal investigations should be recommended for patients with a confirmed diagnosis of IDA.

Epidemiology of iron deficiency anaemia in four European countries: a population-based study in primary care.

OBJECTIVES: Iron deficiency anaemia (IDA) is a global public health concern, being responsible for about 800 000 deaths per year worldwide. To date, few studies have investigated the epidemiology of IDA in Europe. This study therefore aimed to assess the incidence rate and determinants of IDA in four European countries. METHODS: Demographic and clinical information was obtained from four national primary care databases, respectively, for Italy, Belgium, Germany and Spain. IDA-related determinants were estimated using multivariable Cox regression. RESULTS: The annual incidence rates of IDA ranged between 7.2 and 13.96 per 1000 person-years. The estimates were higher in Spain and Germany. Females, younger and older patients were at greater risk of IDA, as well as those suffering from gastrointestinal diseases, pregnant women and those with history of menometrorrhagia, and aspirin and/or antacids users. A Charlson Index >0 was a significant determinant of IDA in all countries. CONCLUSIONS: The use of primary care databases allowed us to assess the incidence rate and determinants of IDA in four European countries. Given the crucial role of general practitioners in the diagnosis and management of this condition, our findings may contribute to increase the awareness of IDA among physicians as well as to reduce its occurrence among at-risk patients.

Italian psychiatrists' perception on cognitive symptoms in major depressive disorder.

OBJECTIVE: Differently than Schizophrenia, the investigation of cognitive impairment in bipolar disorder and major depressive disorder (MDD) attracted the interest of research only recently. Therefore, it is worth understanding clinicians' perception about cognitive dysfunction in MDD and raising awareness about this issue. METHODS: Between December 2014 and January 2015, 128 Italian psychiatrists participated in an on-line survey aiming at understanding psychiatrists' perception about cognitive symptoms in MDD. The questionnaire comprised three sections: the first investigating psychiatrists' socio-demographic profile, the second assessing cognitive symptoms relevance without mentioning that they represented the study focus and the third explicitly investigating cognitive symptoms. RESULTS: Cognitive symptoms were considered as a relevant dimension of MDD and appeared among the most frequently cited residual symptoms influencing patients' work and relapse risk. About 70% of psychiatrists declared that cognitive symptoms significantly influence antidepressant choice. However, in the second questionnaire section cognitive symptoms appeared less frequently considered for antidepressant choice. CONCLUSIONS: Results revealed a clear understanding of cognitive symptoms relevance in MDD. Nevertheless, the discrepancy between psychiatrists' perception and their therapeutical choices underlines the presence of an unmet-need that should be addressed increasing the awareness about the positive effects on cognitive symptoms of existing drugs, which could allow a more symptom-oriented therapeutical intervention. Key points Major depressive disorder (MDD) is a common mental disorder often associated with deficits in cognitive function. Psychiatrists considered cognitive symptoms among the most relevant residual symptoms in MDD patients that compromise patients working and influence the relapse risk. The importance given to residual cognitive symptoms seemed not to be reflected by psychiatrists' therapeutical choice. There is a gap between what psychiatrists know and what psychiatrists apply to their clinical practice reflecting the feeling of a therapeutical unmet need.

Description and management of patients with anal fissure: insights on Italian primary care setting coming from real-world data.

To describe patients with anal fissure (AF) and their management in primary care. Retrospective study using the Italian Longitudinal Patient Database on 18 + years old subjects with AF records during 'July 2016-June 2021' (selection period). Index Date (ID) was the first AF record during selection period. Sub-cohorts were defined by presence/absence of prescriptions on ID of the combination of topical nifedipine 0.3% and lidocaine 1.5% (NIF/LID). Patients' information on the 12-month period before (baseline) and after (follow-up) ID was analyzed. Subjects with AF were 8632: 14.0% had NIF/LID on ID. Mean age was 52 (± 17.2) years, there were more women in ' < 50 years' group, and more men in '50-70' one. Prevalences of pregnancy and immunodepression were around 5%; most common comorbidities were hypertension (29.6%) and heart disease (13.1%), while constipation and diarrhea were < 5%. Healthcare resources utilization (HRUs) increased during follow-up, but still few patients were prescribed NIF/LID (2.8%), other treatments for AF (10.3%), or proctological visits (7.7%). NIF/LID patients were younger (< 40 years people: 30.7% versus 23.9%; p value < 0.0001), and more likely to have constipation (4.3% versus 2.5%; p value < 0.001); patients without NIF/LID showed slightly higher prevalences of hypertension (30.0% versus 27.1%; p value: 0.039) and depression (4.0% versus**2.5%; p value: 0.009), and a little higher overall HRUs. Results show that general practitioners are used to manage AF. However, there is still a gap between guidelines' recommendations and actual management. Educational campaigns on common anal problems in primary care might help further improving AF management and optimizing HRUs.

Extemporaneous combination therapy with nebivolol/ramipril for the treatment of hypertension: a real-world evidence study in Europe.

OBJECTIVES: To describe the clinical characteristics and treatment adherence in European adult hypertensive patients starting treatment with the extemporaneous combination of nebivolol and ramipril (NR-EXC). METHODS: Retrospective database analysis of patients receiving NR-EXC treatment across five European countries (Italy, Germany, France, Poland, Hungary) over a period ranging from 3 to 9 years (until 30 June 2020) according to data availability for the different data sources. Patient demographics, comorbidities, and treatment adherence were evaluated. RESULTS: We identified 592,472 patients starting NR-EXC. Most of them were over 60 years of age, with ramipril most commonly prescribed at 5 mg (from 30.0 to 57.2% of patients across the databases). Notable comorbidities included diabetes (19.2%) and dyslipidemia (18.2%). The study population was also highly subjected to polytherapy with antithrombotics, lipid-lowering agents, and other lowering blood pressure agents as the most co-prescribed medications, as resulted from Italian database. Up to 59% of the patients did not request a cardiologic visit during the study period. Adherence to therapy was low in 56.3% of the patients, and it was high only in 11.1% of them. CONCLUSIONS: The combination of nebivolol and ramipril is frequently prescribed in Europe, but adherence to treatment is suboptimal. The transition to a single pill combination could enhance treatment adherence and streamline regimens, potentially leading to significant benefits. Improved adherence not only correlates with better blood pressure control but also reduces the risk of cardiovascular events, underscoring the importance of this development.

Extemporaneous combination therapy with nebivolol/valsartan for the treatment of hypertension: a study of real-world evidence in Europe.

OBJECTIVE: To explore real-life use of the extemporaneous combination of nebivolol and valsartan (NV-EXC) in adult hypertensive patients in Europe. METHODS: Retrospective analysis of patients starting NV-EXC treatment conducted using prescription databases in Italy, Germany, Hungary, and Poland. The selection period during which study patients were identified covered a time span ranging from 3 to 9 years (until 30 June 2020) according to availability of the different data sources. Patient demographics, clinical information, and treatment adherence, measured by proportion of days covered, were evaluated. Additionally, the potential eligibility of Italian patients for the single pill combination (SPC) of nebivolol and valsartan over a one-year period was estimated. RESULTS: The study included 170,682 patients initiating NV-EXC across the databases. Most patients were females (from 51 to 60%) and primarily aged over 60 years. Few patients received prescriptions of both available dosages of valsartan (80 and 160 mg) during follow-up (from 3.2 to 8.5%). Common comorbidities included dyslipidemia (19.2%) and diabetes (19.1%). Around 59.5% of patients did not require cardiologic visits during the study period. Adherence to NV-EXC, as indicated by the Italian database, was low in 53.3% of patients, with only 16.1% showing high adherence. The Italian database revealed 680 prevalent NV-EXC users in 2019, estimating a potential 30,222 adult patients eligible for the nebivolol/valsartan SPC. CONCLUSIONS: The combination of nebivolol and valsartan is frequently prescribed for hypertension, but adherence remains a challenge. A potential nebivolol/valsartan SPC holds promise in enhancing adherence and optimizing therapeutic outcomes for hypertension management.

Extemporaneous combination therapy with nebivolol/amlodipine for the treatment of hypertension: a real-world evidence study in Europe.

OBJECTIVE: The investigation of the real-world use of the extemporaneous combination of nebivolol and amlodipine (NA-EXC) in adult patients diagnosed with hypertension in Europe. METHODS: Retrospective analysis of data extracted from seven databases of patient medical records and prescriptions from Italy, Germany, France, Hungary, and Poland, to determine the prevalence and incidence of NA-EXC use and to estimate the number of patients potentially eligible for a single-pill combination of the two antihypertensives. Secondary objectives included: the description of the population of NA-EXC users and the assessment of their adherence to treatment based on the proportion of days covered. RESULTS: The use of NA-EXC was found to be common in Europe and ranged between 2.9% to 9.9% of all patients identified in the databases with a prescription of nebivolol and/or amlodipine. The estimated numbers of patients potentially eligible in 2019 for a single-pill combination of nebivolol and amlodipine in Italy and Germany were, respectively, 178,133 and 113,240. Users of NA-EXC were mostly aged 70-79 years, had metabolic disorders and other comorbidities; >70% of them had received ≥2 concomitant medications before starting NA-EXC. Adherence to NA-EXC was defined as high only in 15.6% to 35% of patients. CONCLUSIONS: The extemporaneous combination of nebivolol and amlodipine is commonly prescribed in Europe, however adherence to the therapy is poor. The development of a single-pill combination of nebivolol and amlodipine may improve adherence by reducing the number of pills administered to patients and thus simplifying treatment regimens.

Extemporaneous combination of donepezil and memantine to treat dementia in Alzheimer disease: evidence from Italian real-world data.

OBJECTIVE: Providing evidence on donepezil and memantine administration as extemporaneous combination (DM-EXT) to treat Alzheimer Disease (AD) in Italy, and describing demographic and clinical features of AD patients prescribed DM-EXT. METHODS: Retrospective observational study using IQVIA Italian LifeLink Treatment Dynamics (LRx) and Longitudinal Patient Database (LPD). Prevalent users of DM-EXT were identified on the databases (cohorts DMpLRx and DMpLPD) including patients with donepezil and memantine overlapping prescriptions during the selection period (DMpLRx: "July 2018-June 2021"; DMpLPD: "July 2012-June 2021"). Demographic and clinical profiles of patients were provided. Starting from cohort DMpLPD, new users of DM-EXT were selected to calculate treatment adherence. Three additional cohorts of prevalent users of DM-EXT were identified on IQVIA LRx over subsequent 12-month periods, from July 2018 to June 2021, to get national-level yearly estimates accounting for database representativeness. RESULTS: Cohorts DMpLRx and DMpLPD included 9862 and 708 patients, respectively. For both cohorts, two-third of patients were female, and more than half were aged 80+. Concomitant conditions and co-treatments prevalence was very high; most frequent comorbidities included psychiatric and cardiovascular diseases. An intermediate-to-high adherence was observed in 57% of DM-EXT new users. National-level yearly estimates showed an increasing trend (+4%) in DM-EXT prescription, which led to estimate about 10,000 patients being treated during the period "July 2020-June 2021". CONCLUSIONS: Prescription of DM-EXT is a common practice in Italy. Because the administration of fixed-dose (FDCs) instead of extemporaneous combinations improves treatment adherence, the introduction of an FDC containing donepezil and memantine might enhance AD patients' management and reduce caregiver burden.

Extemporaneous combination therapy with amlodipine/zofenopril in hypertensive patients: a real-world data analysis in Italy.

OBJECTIVES: To provide clinical characteristics and to quantify the number of patients receiving the extemporaneous combination of the calcium channel blocker amlodipine and the angiotensin converting enzyme inhibitor zofenopril in a real-world setting. This evidence can provide a snapshot of the potential users of the two molecules in a single pill combination (SPC). METHODS: Retrospective observational study using data from the IQVIA Italian Longitudinal Patient Database. Adult patients firstly prescribed with amlodipine and zofenopril between 1 July 2011 and 30 June 2020 were identified and demographic and clinical characteristics were extracted. Treatment adherence was evaluated as proportion of days covered (PDC). The potential number of patients eligible for a SPC was calculated. RESULTS: A population of 2394 hypertensive patients, mean age of 68.6 years ±12.7, 52.6% male were treated with amlodipine and zofenopril. The majority of patients (54.5%) were low adherent (PDC <40%), 25.9% were intermediate adherent and only 19.6% were high adherent (>80%) to therapy. Around 42,500 adult hypertensive patients were estimated to be prescribed the extemporaneous combination in 2019 in Italy, being potentially eligible for treatment with amlodipine and zofenopril SPC. CONCLUSIONS: The administration of the extemporaneous combination of zofenopril and amlodipine in hypertensive patients is a common practice in Italy. The development of a SPC can be a viable treatment option to simplify therapy and to increase adherence in hypertensive patients who are already on the two monotherapies in combination.

Extemporaneous combination therapy with nebivolol/zofenopril in hypertensive patients: usage in Italy.

OBJECTIVE: Clinically describing hypertensive patients initiating nebivolol/zofenopril extemporaneous combination (NZ-EXC) and estimating the number of patients currently receiving NZ-EXC and of those potentially eligible for the fixed-dose combination of the two molecules (NZ-FDC) in Italy. METHODS: This retrospective observational study used data from IQVIA Italian Longitudinal Patient Database (LPD). Adult hypertensive patients firstly prescribed NZ-EXC between 1 July 2011 and 30 June 2020 were identified and their demographic and clinical characteristics were extracted. Treatment adherence was evaluated as proportion of days covered (PDC) and classified as low (PDC <40%), intermediate (PDC ≥40% and <80%) or high (PDC ≥80%). Two additional cohorts were identified in 2019 to provide the national-level yearly estimates of patients prescribed NZ-EXC and of patients eligible for NZ-FDC. RESULTS: In total 1745 patients were prescribed NZ-EXC: 60% were women; mean age was 65 years. The most frequent comorbidities were dyslipidemia (19.0%), diabetes (15.5%) and thyroid diseases (13.1%); the most common co-prescribed treatments were antithrombotics (29.1%), lipid-lowering agents (28.8%), nonsteroidal anti-inflammatory drugs (26.1%) and antihyperglycemic agents (13.5%). Mean PDC was 39%, and 57% of the patients had a PDC < 40%. The yearly estimate of patients prescribed NZ-EXC in 2019 was 59,000, while potential users of NZ-FDC were estimated to be 29,000. CONCLUSIONS: NZ-EXC in hypertensive patients is a common practice in Italy and the development of a NZ-FDC can be a viable treatment option for hypertensive patients who are already receiving nebivolol and zofenopril through the concomitant assumption of two distinct pills. As supported by scientific literature, FDCs of antihypertensive drugs could simplify treatment, improve adherence and potentially reduce health-care costs as related to a better control of blood pressure.

The Burden of Short-Acting ß2-Agonist Use in Asthma: Is There an Italian Case? An Update from SABINA Program.

INTRODUCTION: Preliminary results from the SABINA (SABA use IN Asthma) program showed lower overuse of short-acting ß2-agonist (SABA) in Italy compared to other European countries. The aim of the present study was to ascertain whether SABINA's results might have been affected by the Italian National Health System and pharmaceutical market dynamics, by examining patients' characteristics in relation to SABA prescription/purchase habits. METHODS: Multiple approaches were used: (1) a retrospective study using the General Practitioners' (GPs) Italian IQVIA Longitudinal Patient Database (LPD) to assess SABA overuse (more than two canisters/year) and its association with exacerbation risk; (2) a survey conducted across 200 Italian pharmacies to calculate the proportions of SABA purchases without a prescription; (3) a cross-sectional study on the specialists' IQVIA Patient Analyzer database to understand the SABA prescription habits of specialists. RESULTS: Among SABA users identified through IQVIA LPD, the proportion of patients having more than two SABA canisters/year was 32%. Overall, patients prescribed more than two SABA canisters/year by GPs had 30% higher risk of exacerbations than patients with a maximum of two SABA canisters/year. The joint evaluation of IQVIA LPD and survey's findings revealed that IQVIA LPD tracks three out of four SABA canisters dispensed. The survey showed that, on average, SABA users purchased four canisters/year. Patients prescribed SABA by specialists were more frequently men, younger, thinner, and had higher spirometry values. CONCLUSION: SABA overuse is common in Italy, with a share of consumption not regulated by medical prescriptions. Because SABA overuse increases exacerbation risk, changes to national guidelines should be encouraged to ensure implementation of global recommendations.

Living near major traffic roads and risk of deep vein thrombosis.

BACKGROUND: Particulate air pollution has been consistently linked to increased risk of arterial cardiovascular disease. Few data on air pollution exposure and risk of venous thrombosis are available. We investigated whether living near major traffic roads increases the risk of deep vein thrombosis (DVT), using distance from roads as a proxy for traffic exposure. METHODS AND RESULTS: From 1995 through 2005, we examined 663 patients with DVT of the lower limbs and 859 age-matched controls from cities with population >15 000 inhabitants in Lombardia Region, Italy. We assessed distance from residential addresses to the nearest major traffic road using geographic information system methodology. The risk of DVT was estimated from logistic regression models adjusting for multiple clinical and environmental covariates. The risk of DVT was increased (odds ratio=1.33; 95% confidence interval, 1.03 to 1.71; P=0.03 in age-adjusted models; odds ratio=1.47; 95% confidence interval, 1.10 to 1.96; P=0.008 in models adjusted for multiple covariates) for subjects living near a major traffic road (index distance of 3 meters, 10th centile of the distance distribution) compared with those living farther away (reference distance of 245 meters, 90th centile). The increase in DVT risk was approximately linear over the observed distance range (from 718 to 0 meters) and was not modified after adjusting for BACKGROUND: =0.008 for 10th versus 90th distance centile in models adjusting for area levels of particulate matter <10 mum in aerodynamic diameter in the year before diagnosis). CONCLUSIONS: Living near major traffic roads is associated with increased risk of DVT.

Airborne particulate matter and mitochondrial damage: a cross-sectional study.

UNLABELLED: Oxidative stress generation is a primary mechanism mediating the effects of Particulate Matter (PM) on human health. Although mitochondria are both the major intracellular source and target of oxidative stress, the effect of PM on mitochondria has never been evaluated in exposed individuals. METHODS: In 63 male healthy steel workers from Brescia, Italy, studied between April and May 2006, we evaluated whether exposure to PM was associated with increased mitochondrial DNA copy number (MtDNAcn), an established marker of mitochondria damage and malfunctioning. Relative MtDNAcn (RMtDNAcn) was determined by real-time PCR in blood DNA obtained on the 1st (time 1) and 4th day (time 2) of the same work week. Individual exposures to PM10, PM1, coarse particles (PM10-PM1) and airborne metal components of PM10 (chromium, lead, arsenic, nickel, manganese) were estimated based on measurements in the 11 work areas and time spent by the study subjects in each area. RESULTS: RMtDNAcn was higher on the 4th day (mean = 1.31; 95%CI = 1.22 to 1.40) than on the 1st day of the work week (mean = 1.09; 95%CI = 1.00 to 1.17). PM exposure was positively associated with RMtDNAcn on either the 4th (PM10: beta = 0.06, 95%CI = -0.06 to 0.17; PM1: beta = 0.08, 95%CI = -0.08 to 0.23; coarse: beta = 0.06, 95%CI = -0.06 to 0.17) or the 1st day (PM10: beta = 0.18, 95%CI = 0.09 to 0.26; PM1: beta = 0.23, 95%CI = 0.11 to 0.35; coarse: beta = 0.17, 95%CI = 0.09 to 0.26). Metal concentrations were not associated with RMtDNAcn. CONCLUSIONS: PM exposure is associated with damaged mitochondria, as reflected in increased MtDNAcn. Damaged mitochondria may intensify oxidative-stress production and effects.

Hemolytic disease of the fetus and newborn due to Rh(D) incompatibility: A preventable disease that still produces significant morbidity and mortality in children.

In the mid-20th century, Hemolytic Disease of the Fetus and Newborn, caused by maternal alloimmunization to the Rh(D) blood group antigen expressed by fetal red blood cells (i.e., "Rh disease"), was a major cause of fetal and neonatal morbidity and mortality. However, with the regulatory approval, in 1968, of IgG anti-Rh(D) immunoprophylaxis to prevent maternal sensitization, the prospect of eradicating Rh disease was at hand. Indeed, the combination of antenatal and post-partum immunoprophylaxis is ~99% effective at preventing maternal sensitization to Rh(D). To investigate global compliance with this therapeutic intervention, we used an epidemiological approach to estimate the current annual number of pregnancies worldwide involving an Rh(D)-negative mother and an Rh(D)-positive fetus. The annual number of doses of anti-Rh(D) IgG required for successful immunoprophylaxis for these cases was then calculated and compared with an estimate of the annual number of doses of anti-Rh(D) produced and provided worldwide. Our results suggest that ~50% of the women around the world who require this type of immunoprophylaxis do not receive it, presumably due to a lack of awareness, availability, and/or affordability, thereby putting hundreds of thousands of fetuses and neonates at risk for Rh disease each year. The global failure to provide this generally acknowledged standard-of-care to prevent Rh disease, even 50 years after its availability, contributes to an enormous, continuing burden of fetal and neonatal disease and provides a critically important challenge to the international health care system.

Differential repetitive DNA methylation in multiple myeloma molecular subgroups.

Multiple myeloma (MM) is characterized by a wide spectrum of genetic changes. Global hypomethylation of repetitive genomic sequences such as long interspersed nuclear element 1 (LINE-1), Alu and satellite alpha (SAT-alpha) sequences has been associated with chromosomal instability in cancer. Methylation status of repetitive elements in MM has never been investigated. In the present study, we used a quantitative bisulfite-polymerase chain reaction pyrosequencing method to evaluate the methylation patterns of LINE-1, Alu and SAT-alpha in 23 human myeloma cell lines (HMCLs) and purified bone marrow plasma cells from 53 newly diagnosed MM patients representative of different molecular subtypes, 7 plasma cell leukemias (PCLs) and 11 healthy controls. MMs showed a decrease of Alu [median: 21.1 %5-methylated cytosine (%5mC)], LINE-1 (70.0%5mC) and SAT-alpha (77.9%5mC) methylation levels compared with controls (25.2, 79.5and 89.5%5mC, respectively). Methylation levels were lower in PCLs and HMCLs compared with MMs (16.7 and 14.8%5mC for Alu, 45.5 and 42.4%5mC for LINE-1 and 33.3 and 43.3%5mC for SAT-alpha, respectively). Notably, LINE-1 and SAT-alpha methylation was significantly lower in the non-hyperdiploid versus hyperdiploid MMs (P = 0.01 and 0.02, respectively), whereas Alu and SAT-alpha methylation was significantly lower in MMs with t(4;14) (P = 0.02 and 0.004, respectively). Finally, we correlated methylation patterns with DNA methyltransferases (DNMTs) messenger RNA levels showing in particular a progressive and significant increase of DNMT1 expression from controls to MMs, PCLs and HMCLs (P < 0.001). Our results indicate that global hypomethylation of repetitive elements is significantly associated with tumor progression in MM and may contribute toward a more extensive stratification of the disease.