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Background: Little is known about the comparative risk of death with atypical or conventional antipsychotics (APs) among persons with cardiovascular or cerebrovascular disease (CCD). Research design and methods: A cohort study was conducted using five Italian claims databases. New atypical AP users with CCD aged ≥65 (reference) were matched to new conventional AP users. Mortality per 100 person-years (PYs) and hazard ratios (HR), estimated using Cox models, were reported. Incidence and risk of death were estimated for persons having drug–drug interactions. Outcome occurrence was evaluated 180 days after AP initiation. Results: Overall 24,711 and 27,051 elderly new conventional and atypical AP users were identified. The mortality rate was 51.3 and 38.5 deaths per 100 PYs for conventional and atypical AP users. Mortality risk was 1.33 (95%CI: 1.27–1.39) for conventional APs. There was no increased mortality risk with single drug–drug interactions (DDIs) vs. no DDI. AP users with ≥1 DDI had a 29% higher mortality risk compared to no DDI in the first 90 days of treatment (HR: 1.29 (95% CI: 1.00–1.67)). Conclusions: Conventional APs had a higher risk of death than atypical APs among elderly persons with CCD. Having ≥1 DDI was associated with an increased risk of death.

Enormous progress has been made globally in the use of evidence derived from patients’ clinical information as they access their routine medical care. The value of real-world data lies in their complementary nature compared with data from randomised controlled trials: less detailed information on drug efficacy but longer observational periods and larger, more heterogeneous study populations reflecting clinical practice because individuals are included who would not usually be recruited in trials. Real-world data can be collected in various types of electronic sources, such as electronic health records, claims databases and drug or disease registries. These data sources vary in nature from country to country, according to national healthcare system structures and national policies. In Italy, a growing number of healthcare databases have been used to evaluate post-marketing drug utilisation and safety in the last two decades. The aim of this narrative review is to describe the available Italian sources of real-world data and their contribution to generating post-marketing evidence on drug use and safety. We also discuss the strengths and limitations of the most commonly used Italian healthcare databases in addressing various research questions concerning drug utilisation, comparative effectiveness and safety studies, as well as health technology assessment and other areas.

Objective: The objective of this study was to investigate the relationship between adherence to statin therapy and the risk of exacerbation among elderly individuals affected by chronic obstructive pulmonary disease and cardiovascular disease. Methods: Using the healthcare utilisation databases of five Italian territorial units accounting for nearly 35% of the Italian population, we recruited a cohort of 6263 elderly persons (i.e. aged 65 years or older) with co-existing chronic obstructive pulmonary disease and cardiovascular disease who initiated statin therapy. Exposure was adherence to statins measured by the proportion of days of follow-up covered. Outcome was the first hospital admission for chronic obstructive pulmonary disease occurring in the period of observation. A proportional hazards model was used to estimate the hazard ratio and 95% confidence intervals for the exposure–outcome association, after adjusting for several covariates. A set of sensitivity analyses was performed to account for sources of systematic uncertainty. Results: During an average follow-up of about 4 years, 1307 cohort members experienced the outcome. Compared with patients with low adherence (proportion of days of follow-up covered ≤ 40%), those with intermediate (proportion of days of follow-up covered 41–80%) and high (proportion of days of follow-up covered > 80%) adherence exhibited a lower risk of exacerbation of 16% (95% confidence interval 3–27) and 23% (95% confidence interval 10–34). Conclusions: In a real-world setting, we observed evidence that adherence to statin therapy markedly reduced the risk of chronic obstructive pulmonary disease exacerbations in elderly patients with co-existing chronic obstructive pulmonary disease and cardiovascular disease. Given the limited and controversial evidence from trials, more randomised controlled trials are urgently needed to better examine the potential benefits of statins as adjunct therapy in chronic obstructive pulmonary disease.

Background and Objective: Conflicting findings from studies evaluating the association between use of antidepressant drugs and mortality have been reported. We tested the hypothesis that better adherence to antidepressant therapy may reduce mortality. Methods: The cohort included 29,845 individuals aged ≥ 65 years from several Italian health units who were newly treated with antidepressant drugs after hospital discharge with a diagnosis for cardiovascular disease during 2008–2010. These individuals were observed from the first prescription until the end of data availability (i.e. 2012–2014, depending on the local database). During this period, information on (1) prescription of antidepressants and other medications and (2) death from any cause (outcome) was recorded. Proportional hazards models were fitted to estimate the association between better adherence to antidepressants (defined as proportion of days covered ≥ 75%) and outcome, by adjusting and stratifying for several covariates. Results: Patients with better adherence to antidepressants had a reduced mortality of 9% (95% CI 3–14). Patients who did not use other medicaments during follow-up had reduced mortality associated with better adherence to antidepressants of 21% (− 1–38), 14% (7–20), 20% (13–26) and 13% (7–19) for no users of antihypertensive agents, lipid-lowering agents, other cardiovascular drugs and antidiabetics, respectively. Conclusions: Better adherence to antidepressants is associated with reduced all-cause mortality, mainly in patients who did not use other pharmacological treatments. Behavioural changes to enhance adherence among the elderly with cardiovascular disease might offer important benefits in reducing their mortality.

BACKGROUND: In pharmacovigilance, spontaneous reporting databases are devoted to the early detection of adverse event 'signals' of marketed drugs. A common limitation of these systems is the wide number of concurrently investigated associations, implying a high probability of generating positive signals simply by chance. However it is not clear if the application of methods aimed to adjust for the multiple testing problems are needed when at least some of the drug-outcome relationship under study are known. To this aim we applied a robust estimation method for the FDR (rFDR) particularly suitable in the pharmacovigilance context. METHODS: We exploited the data available for the SAFEGUARD project to apply the rFDR estimation methods to detect potential false positive signals of adverse reactions attributable to the use of non-insulin blood glucose lowering drugs. Specifically, the number of signals generated from the conventional disproportionality measures and after the application of the rFDR adjustment method was compared. RESULTS: Among the 311 evaluable pairs (i.e., drug-event pairs with at least one adverse event report), 106 (34%) signals were considered as significant from the conventional analysis. Among them 1 resulted in false positive signals according to rFDR method. CONCLUSION: The results of this study seem to suggest that when a restricted number of drug-outcome pairs is considered and warnings about some of them are known, multiple comparisons methods for recognizing false positive signals are not so useful as suggested by theoretical considerations.

Background: Reforms introduced in the last decade in Italian general practice, have contributed to the changing role of primary care physicians (PCPs) within the Italian National Health Service, with potential difficulties adapting that may lead to job stress and dissatisfaction. The present study aims to compare job satisfaction and stress levels of PCPs working in primary healthcare teams (PHCTs) with those for practitioners operating in single ambulatory offices, and to assess potential associations with aspects of job and practice management. Method A postal survey was conducted between January and March 2005 among PCPs working in Tuscany. Data were collected by using a structured questionnaire containing questions concerning personal, professional, job and practice characteristics. The Warr-Cook-Wall scale and the Cooper test were used to assess job satisfaction and stress, respectively. Results: From 3043 PCPs, a response rate of 45.2% was achieved. Significant differences were found between PHCT physicians and solo practitioners in several aspects of their job. Physicians working in PHCTs appeared more satisfied in some aspects of their practice such as organisation, whereas they were less satisfied about workload and interaction with other healthcare providers. Multivariate modelling showed relevant aspects of dissatisfaction and stress, particularly the difficulties of collaboration with other healthcare providers, and access to specialised services. Conclusion: Reform strategies aimed at improving the quality of care among PCPs needs to take into account the contextual determinants of physician satisfaction and stress, and should highlight programmes that might be pursued to improve the integration of PCPs within the Italian National Health System.

Background: Fluoroquinolones are widely used both in primary care and in hospital settings. Since the last comparison performed in Italy on the safety profiles of different fluoroquinolones, a new molecule, prulifloxacin, has been introduced into the market and several warnings concerning this class of drugs have been released. The aim of this study was to reassess the safety profiles of fluoroquinolones using the database of the Italian Interregional Group of Pharmacovigilance (IGP) and the administrative data of fluoroquinolone prescriptions. Methods: All adverse drug reactions (ADRs) reported in four Italian regions (Lombardy, Veneto, Emilia Romagna and Tuscany) were retrieved from the IGP database. Consumption data (defined daily dose [DDD]/1000 inhabitants/ day) were used as denominators. Both single reports and all ADRs (classified by System Organ Classes and MedDRA Preferred Term [PT]) due to fluoroquinolones were considered as numerators of each analysis, comparing two periods (2005 vs 2006). All fluoroquinolones with at least ten reports per year were included in the analysis. Results: On the basis of 272 reports (532 single ADRs or PTs), patients did not show any statistically significant differences between 2005 and 2006 in terms of sex, age and number of concurrent medications. After adjustment for drug consumption, moxifloxacin showed the highest reporting rate (84.6 reports/ DDD/1000 inhabitants/day; 15.4 serious reports/DDD/1000 inhabitants/day) followed by prulifloxacin (72.2; 22.2 serious) and levofloxacin (55.3; 30.6serious) in 2005. An increment of ADR/report rates was observed over the 2 years for all fluoroquinolones except prulifloxacin, which had the lowest ADR reporting rate in 2006 (25.0; 12.5 serious). In 2006, the rate of serious ADRs associated with prulifloxacin was lower than with ciprofloxacin, while in 2005 serious events were almost equal for both compounds (55.6 vs 47.6 serious ADRs/DDD/1000 inhabitants/day). Ciprofloxacin showed the highest proportion of cutaneous PTs (e.g. rash, exanthema). Tendinopathies were mainly due to levofloxacin. Conclusions: These data suggest that different fluoroquinolones are characterized by different rates and types of ADRs. Among them, prulifloxacin was associated with more ADRs than other fluoroquinolones in 2005 but with fewer ADRs in 2006, when its consumption increased. Although these findings may represent an encouraging perspective towards a more appropriate use of fluoroquinolones because of their individual safety profiles, further pharmacoepidemiological studies must be performed to substantiate these results. © 2010 Adis Data Information BV. All rights reserved.

Background Data on the effect of oral bisphosphonates (BPs) on risk of upper gastrointestinal complications (UGIC) are conflicting. We conducted a large population-based study from a network of Italian healthcare utilization databases aimed to assess the UGIC risk associated with use of BPs in the setting of secondary prevention of osteoporotic fractures. Methods A nested case–control study was carried out within a cohort of 68,970 patients aged 45 years or older, who have been hospitalized for osteoporotic fracture from 2003 until 2005. Cases were the 804 patients who experienced hospitalization for UGIC until 2007. Up to 20 controls were randomly selected for each case. Conditional logistic regression model was used to estimate odds ratio (OR) associated with current and past use of BPs (i.e. for drug dispensation within 30 days and over 31 days prior the outcome onset, respectively) after adjusting for several covariates. Results Compared with patients who did not use BPs, current and past users had OR (and 95% confidence interval) of 0.86 (0.60 to 1.22) and 1.07 (0.80 to 1.44) respectively. There was no difference in the ORs estimated according with BPs type (alendronate or risedronate) and regimen (daily or weekly), nor with co-therapies and comorbidities. Conclusions Further evidence that BPs dispensed for secondary prevention of osteoporotic fractures are not associated with increased risk of severe gastrointestinal complications is supplied from this study. Further research is required to clarify the role BPs and other drugs of co-medication in inducing UGIC.

We aimed to develop and validate the FRActure Health Search (FRA-HS) score for prediction of risk of osteoporotic fractures in primary care in Italy. We selected a cohort of patients aged 40 years between 1999 and 2002. They were followed until the occurrence of osteoporotic fracture, death, end of data registration, or end of data availability (December 31, 2012). Age, sex, history of osteoporotic fractures, secondary osteoporosis, long-term use of corticosteroids, rheumatoid arthritis, body mass index, smoking, and alcohol abuse/alcohol-related diseases, and the interaction terms sex*use of corticosteroids and age*secondary osteoporosis were entered in a competing-risk regression (Fine and Gray method) to predict the risk of hip/femur or overall major osteoporotic fractures. The coefficients were combined to obtain the FRA-HS for individual patients. Explained variance, discrimination, and calibration measures were computed to evaluate the models accuracy. The final model was tested using an independent data source. The FRA-HS explained 47.36 and 20.6% of the variation for occurrence of hip/femur and overall major osteoporotic fractures, respectively. Area Under Curve was 0.77 and 0.73, respectively. Predicted/observed ratios revealed a margin of error lower than 30% in the 80% of the population. After stratifying by sex, prediction models for hip/femur fractures confirmed acceptable accuracy in both sexes, while poor explained variance (

Purpose: To assess the gender and age-related 5-year incidence rates of osteoporotic fractures, and their related predictors, in a primary care setting. Methods: We obtained information from the Health Search-CSD Longitudinal Patients Database (HSD). This is an Italian General Practice data repository which comprises information given by computer-based patient records of a selected group of over 900 Primary Care Physicians (PCPs). We selected all patients aged 50 to 85 years, who were actively included into the PCP's list at the beginning of the enrolment period (1st January 2002-31st December 2003). We excluded individuals who were registered in the PCPs' list for less than 1 year before the entry date (Index date) into the cohort, as well as those who were diagnosed with Paget disease or malignant neoplasm. Participants were followed up until the occurrence of osteoporotic fracture, one of the exclusion criteria, or the end of the study period. Results: The 5-year rates (per 1000 person-years) of any osteoporotic fracture were 11.56 (95% C.I. 11.33 to 11.77) among females, and 4.91 (95% C.I. 4.75 to 5.07) among males. For hip fractures, the overall incidence rates were 3.23 (95% C.I. 3.11 to 3.34) among females and 1.21 (95% C.I. 1.12 to 1.28) among males, respectively. Advanced age, history of fracture, use of corticosteroids, rheumatoid arthritis, BMI

Purpose Mostly because of comorbidity and drugs consumption, older persons are often exposed to an increased risk of sub-optimal prescribing (SP). At present, few studies investigated the association between SP and long-term health outcomes. We examined the relation between SP and the risk of mortality and hospitalization in Italian older community-dwellers. Methods Older (65+ years) community-dwelling residents of a small town in Tuscany were enrolled in a longitudinal study. SP was defined as polypharmacy (use of 5+ drugs), prescription of inappropriate drugs (ID) according to Beers' criteria, and of potentially interacting drugs (PID), evaluated in 1995 and 1999. These three forms of SP were entered as time-dependent exposures into multivariable Cox regression analysis models, whose outcomes were mortality and hospitalizations through 2003. Results Of 1022 participants (mean age 73.0 ± 6.8, 57% women), 220 were evaluated in 1995, 234 in 1999 and 568 in both waves. In univariate analysis, mortality was two-fold higher in participants with polypharmacy (73.4/1000 person/years, 95% CI 58.2–92.4 vs. 34.1, 95% CI 29.7–39.2; p

Systematic assessment of blood pressure (BP) control rates may help to improve the clinical management of hypertension in clinical practice. This approach had limited application in Europe over the last three decades and only recently has been implemented in some countries. The present study is aimed at evaluating hypertension prevalence and control among adult outpatients followed by a large, representative sample of general practitioners (GPs) in Italy. We retrospectively analysed the data derived from the GP Health Search-CSD database in 2013. Hypertension prevalence and control were estimated within the overall population sample and in hypertensive outpatients, respectively, according to age and gender. Hypertension diagnosis was defined according to the International Classification of Diseases 9. Clinic BP levels were measured according to the European guidelines. BP control was defined as systolic/diastolic BP

Purpose: The effect of drug exposure misclassification generally receives little attention in pharmacoepidemiological research. In this paper, we illustrate a probabilistic bias analysis approach for misclassified categorical exposures and apply it in a database study of oral anti-hyperglycaemic drugs (OADs). Methods: A cohort study based on the Health Search Database general-practice database was carried out by including 12 640 adult (≥40 years) patients newly treated with OADs during 2003–2010. The proportion of days covered by OADs prescriptions during the first year of follow-up was evaluated for each individual, either by means of the prescribed daily dose or the defined daily dose. The effect of misclassification on hypothetical OAD–outcome association profiles was assessed through the proposed probabilistic bias analysis approach, taking advantage of available exposure validation data. Results: During the first year of follow-up, the average (SD) number of months with OADs available was 7 (4) months and 5 (3) months according to the prescribed daily dose and defined daily dose metrics, respectively. Probabilistic bias analysis results based on validation data suggest that the effect of misclassification is complex, as conventional exposure–outcome association estimates may be of greater or lower magnitude than their misclassification-adjusted values. Conclusions: Misclassification should be taken into account in database studies on the safety of prescribed medications. To this aim, investigators should take advantage of external exposure validation data in sensitivity analysis approaches such as ours. Copyright © 2016 John Wiley & Sons, Ltd.

Objectives The Italian project MATRICE aimed to assess how well cases of type 2 diabetes (T2DM), hypertension, ischaemic heart disease (IHD) and heart failure (HF) and their levels of severity can be automatically extracted from the Health Search/CSD Longitudinal Patient Database (HSD). From the medical records of the general practitioners (GP) who volunteered to participate, cases were extracted by algorithms based on diagnosis codes, keywords, drug prescriptions and results of diagnostic tests. A random sample of identified cases was validated by interviewing their GPs. Setting HSD is a database of primary care medical records. A panel of 12 GPs participated in this validation study. Participants 300 patients were sampled for each disease, except for HF, where 243 patients were assessed. Outcome measures The positive predictive value (PPV) was assessed for the presence/absence of each condition against the GP9s response to the questionnaire, and Cohen9s κ was calculated for agreement on the severity level. Results The PPV was 100% (99% to 100%) for T2DM and hypertension, 98% (96% to 100%) for IHD and 55% (49% to 61%) for HF. Cohen9s kappa for agreement on the severity level was 0.70 for T2DM and 0.69 for hypertension and IHD. Conclusions This study shows that individuals with T2DM, hypertension or IHD can be validly identified in HSD by automated identification algorithms. Automatic queries for levels of severity of the same diseases compare well with the corresponding clinical definitions, but some misclassification occurs. For HF, further research is needed to refine the current algorithm.

AIMS Although calculation of the global cardiovascular risk is strongly recommended, limited data are available regarding the use and the utility of this tool in clinical practice. We aimed at answering the following questions in the setting of Italian general practice: how many patients are evaluated via the cardiovascular risk algorithm; what are their characteristics; and what happens after their evaluation. METHODS We used the Health Search/CSD Longitudinal Patient Database. The software used by about 800 participating GPs allows the calculation of the global cardiovascular risk in automatic. The following data were yearly extracted from the database within 2004-2008: age, sex, and recorded diagnosis of the main cardiovascular and other information encompassing smoking habits, blood pressure, total cholesterol, high density lipoprotein cholesterol (i.e., variables used to calculate cardiovascular risk), BMI, physical activity, triglycerides, glucose and creatinine; wherever available, current cardiovascular therapy and the automatically computed global cardiovascular risk were also extracted. RESULTS In 2008, the observed population, aged 35-69 years, numbered 438 922 individuals; 78 617 (17.9%) had at least one calculation of cardiovascular risk; 20 181 patients were re-evaluated at least once: 61.1% among high-risk patients, 43.8% among moderate-risk patients, and 27.2% among low-risk patients. The level of cardiovascular risk measured at baseline increased in 6863 (34%), decreased in 11 791 (58.4%), and did not change in 1527 (7.6%) individuals. Overall, mean cardiovascular risk decreased over 4 years in 2.25% (SD 6.41%; P

PURPOSE: The results of an analysis of suspected antiviral-associated adverse drug reactions (ADRs) in Italy over a 22-year period are presented. METHODS: A case/non-case analysis was conducted using ADR reports compiled in the nationwide spontaneous-reporting database through September 2010. All reported events included in the analysis were evaluated and coded by drug safety experts; causality assessments were performed according to the algorithm of Naranjo et al. The association between an adverse reaction and antiviral use was assessed by estimating the reporting odds ratio (ROR), with 95% confidence interval (CI), as a measure of disproportionality. RESULTS: Overall, 863 reports of suspected ADRs involving antivirals and 42,430 reports of adverse reactions to other drugs were identified; of those events, 3.3% and 64.3% were determined to be definite or probable ADRs, respectively, and an additional 32.4% were deemed possibly drug related. Several ADRs were disproportionately associated with antivirals relative to other drugs: renal colic (ROR, 25.5; 95% CI, 13.3-49.0), lactic acidosis (ROR, 18.6; 95% CI, 9.2-37.7), depression (ROR, 18.0; 95% CI, 11.6-27.9), anemia (ROR, 15.9; 95% CI, 12.3-20.4), hallucination (ROR, 4.3; 95% CI, 2.7-7.1), neutropenia (ROR, 4.1; 95% CI, 2.9-5.8), acute renal failure (ROR, 3.9; 95% CI, 2.3-6.4), fever (ROR, 3.8; 95% CI, 2.8-5.1), hyperpyrexia (ROR, 2.9; 95% CI, 1.7-4.9), and asthenia (ROR, 1.8; 95% CI, 1.2-2.8). CONCLUSION: Analysis of data from a large Italian database showed that, among antiviral agents, the ribavirin-interferon combination, acyclovir, valacyclovir, indinavir, and zidovudine accounted for the most serious hematologic, neuropsychiatric, and renal ADRs.

Community-acquired pneumonia (CAP) is a major respiratory health disease with high prevalence in the general population, clinical heterogeneity and different degrees of severity. In both the USA and Europe, CAP is the most frequent cause of infection-related death. Its incidence varies from country to country and from study to study, and it is higher in very young children and elderly persons [1]. A recent UK study documented an increase of 34% in hospital admissions due to CAP over the past decade [2]. Despite the importance of its social impact, actual incidence of CAP in different settings is still under scrutiny. Thus, we aimed to explore the epidemiology of CAP in Italian general practice. We collected data from the Health Search - CSD Patient Database (HSD), an electronic general practice database, representative of the Italian general population, which was set up in 1998 by the Italian College of General Practitioners (Florence, Italy). The HSD contains data from approximately 1.2 million inhabitants under the care of 800 general practitioners (GPs), homogenously distributed across Italy. All clinical diagnoses are coded according to the International Classification of Diseases 9th Revision (ICD-9). Drugs are coded according to the Anatomical Therapeutic and Chemical classification system. The HSD has been extensively used for pharmaco-epidemiologic research

Reduced-intensity conditioning regimens have reshaped the clinical presentation of graft-versus-host disease after hematopoietic stem cell transplants. However, histopathologic features of graft-versus-host disease following reduced-intensity conditioning regimens have not been fully characterized. In a series of 112 biopsies (skin, n = 60; gastrointestinal [GI] tract, n = 44; liver, n = 8), we described the morphologic profile of graft-versus-host disease following reduced-intensity conditioning and investigated whether histopathologic changes of graft-versus-host disease following reduced-intensity conditioning have a diagnostic and/or prognostic value. Forty-four patients (49.5%) experienced acute graft-versus-host disease, 2(2.2%) late-onset acute graft-versus-host disease (grade I, n = 13; grade II-IV, n = 33), 24(27.0%) chronic graft-versus-host disease (de novo n = 12, progressive n = 12) and 19 (21.3%) overlap syndrome. In the skin, we observed: (i) phase-nonspecific changes, such as acute graft-versus-host disease features in chronic graft-versus-host disease patients (n = 4/24; 16.6%), (ii) subtle alterations such as superficial fibrosis in widened dermal papillae (n = 8), in acute graft-versus-host disease/late-onset graft-versus-host disease (n = 6/46; 13.0%) or chronic graft-versus-host disease (n = 2/24, 8.3%) patients, and (iii) features of chronic and acute graft-versus-host disease coexisting in the same specimen in overlap syndrome (n = 3/19; 15.7%). In the GI tract, we did not demonstrate peculiar features differing from those commonly observed in the myeloablative setting. By univariate analysis, a reduced overall survival was associated with graft-versus-host disease type (chronic graft-versus-host disease P = .006, acute graft-versus-host disease P = .03), older age (P = .04), and histopathologic diagnosis of "consistent with" + definite graft-versus-host disease (P = .02). Histopathologic diagnosis retained an independent prognostic value by multivariate analysis (P = .01). The present study indicates that pathologists should be aware of the peculiar morphologic changes of cutaneous graft-versus-host disease following reduced-intensity conditioning and further recommends histopathology in the diagnostic workup of graft-versus-host disease in patients undergoing reduced-intensity conditioning regimen. (C) 2011 Elsevier Inc. All rights reserved.