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Aims Heart failure (HF) and chronic obstructive pulmonary disease (COPD) frequently co-exist, and each is a major public health issue. In a large cohort of hospitalized HF patients, we evaluated: (i) the impact of COPD on clinical outcomes; (ii) whether outcomes and treatments changed from 2002 to 2009; and (iii) the relationship between outcomes and treatments focusing on beta-blockers (BBs) and bronchodilators (BDs). Methods and results From linkable Lombardy administrative health databases, we selected individuals with a discharge diagnosis of HF with or without concomitant COPD (HF yesCOPD and HF noCOPD) in 2002 and 2009. Patients were followed up for 4 years. Outcomes were total mortality, first readmission for HF, and their combination. Unadjusted and adjusted Cox proportional models and competing risk analyses were used. We identified 11 274 patients with HF noCOPD and 2837 with HF yesCOPD. HF yesCOPD patients in 2002 and 2009 had a 20% higher risk of the outcomes. From 2002 to 2009, BB and BD prescriptions increased significantly. In HF noCOPD patients, risks for mortality [adjusted hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.86–0.97], first HF readmission (HR 0.79, 95% CI 0.74–0.85), and the combined endpoint (HR 0.88, 95% CI 0.84–0.92) declined (all P < 0.003) while in HF yesCOPD only the risk for first HF readmission dropped (HR 0.86, 95% CI 0.76–0.97; P = 0.018). BBs were associated with significantly lower mortality in both groups, but with a higher risk for first HF readmission in HF noCOPD. Outcomes did not significantly differ in HF yesCOPD treated or not with BDs. Conclusions The prognosis of patients hospitalized for HF, either with or without COPD, seemed to improve between 2002 and 2009, with possibly better survival of those on BBs. Because of residual confounding in observational studies, a randomized controlled trial should be considered to confirm these results.

Background and objective Real-world evidence suggests that persistence with inhaled corticosteroids (ICS), the mainstay of asthma drug therapy, is generally poor. The effect of persistence with ICS on the risk of asthma exacerbation was addressed in a population-based study. Methods The cohort of 2335 beneficiaries of the National Health Service provided by the Italian Region of Lombardy, aged 18–40 years and newly treated with ICS during 2005–2008, was followed from their first ICS dispensation until 2010. Discontinuation of treatment with ICS and starting oral corticosteroid therapy during follow-up were respectively regarded as proxies of poor persistence with asthma medication and asthma exacerbation (outcomes). A proportional hazards model was fitted to identify predictors of ICS discontinuation. Case-crossover and case-case-time-control designs and conditional logistic regressions were used to estimate the association between persistence with ICS and asthma exacerbation. Results Cumulative incidences of discontinuation were 36%, 57% and 78% at 6 months, 1 year and 5 years, respectively. Predictors of poor persistence were female gender, use of antibiotics during follow-up, absence of use of short-acting beta-agonists prior to and after starting treatment with ICS and starting and maintaining ICS monotherapy during follow-up. The odds ratios of asthma exacerbation (and 95% confidence intervals) associated with ICS exposure during the current period, contrasted with exposure during the reference period, were 0.4 (0.2, 0.9) and 0.3 (0.1, 1.0) from case-crossover and case-case-time-control estimates, respectively. Conclusion Persistence with ICS treatment in adults with asthma reduces the risk of exacerbation in the real-life setting.

To assess the pattern of use of Emergency Departments (EDs), factors contributing to the visits, geographical distribution and outcomes in people aged 65 years or more living in the Italian Lombardy Region in 2012. Based on an administrative database the study population was divided into groups according to the number of ED visits. A multinomial logistic regression model was performed to compare the characteristics of each group. The Getis–Ord’s G statistic was used to evaluate the clusters of high and low visit prevalence odd ratios (OR) at district level. To estimate the severity of the disease leading to ED attendance, visits were stratified based on the level of emergency and outcome. About 2 million older people were included in the analyses: 78 % had no ED visit, 15 % only 1, 7 % 2 or more. Male sex, age 85 years or more, high number of drugs, ED visits and hospital admissions in the previous year and the location of an ED within 10 km from the patient’s place were all factors associated with a higher risk to have more ED visits. Clusters of high and low prevalence of visits were found for occasional users. Overall, 83 % of ED visit with a low emergency triage code at admission had as visit outcome discharge at home. In older people several variables were associated with an increased risk to have a high number of ED visits. Most of the visits were done for non-urgent problems and significant geographic differences were observed for occasional users.

ObjectivesTo evaluate the diagnostic and therapeutic approaches in a cohort of asthmatic children before and after starting drug therapy.MethodsData were retrieved from administrative databases of the Lombardy Region. The study population was composed of 78 184 children born in the Lombardy Region in 2002 and followed until their 10th birthday.Children with at least one antiasthmatic drug prescription per year (with the exclusion of nebulised suspension/solution formulations) in 2 consecutive years and at least one antiasthmatic drug prescription after the fifth birthday were identified as potential asthmatics (PA).Each PA was monitored for a period starting from 12 months before and ending 24 months after the first prescription (index prescription, IP). During the monitoring period antiasthmatic drug prescriptions were analysed, as well as spirometry and/or specialist visits.ResultsA total of 59 975 children (76.7%) received ≥1 prescription of antiasthmatic drugs in their first 10 years of life, and 4475 (5.7%) were identified as PAs. In all, 24% of PAs started with short-acting β2-agonists (SABA), 23% with inhaled corticosteroids (ICS) and 20% with SABA+ICS.A total of 33% of PAs had at least one prescription for specialist visit/spirometry: 11% before and 28% after the IP. The factors associated with a greater likelihood of receiving visit/spirometry prescriptions were local health unit of residence, age and high use of asthma drugs.ConclusionsDespite international guideline recommendations, spirometry monitoring is still underused in asthmatic children, even in subjects who initiated pharmacological treatment and therefore need an airway function evaluation. Moreover, the choice of drug therapy appears not always rational, since one out of four children were commenced on ICS as monotherapy.

Healthcare administrative databases of Italy's Lombardy Region were analyzed with the aim to assess perinatal outcomes and healthcare resource utilization during the first year of life in infants exposed to antiepileptic drugs (AEDs) during pregnancy. Drug prescriptions dispensed in the 12 months before delivery to women, who delivered between 2005 and 2011, were analyzed. Neonates were classified as cases if exposed to AEDs, and each case was randomly matched to seven controls. No significant differences were observed in the risk of congenital malformations between 526 cases and 3682 controls except for valproic acid (odds ratio (OR): 2.29; 95% confidence interval (CI): 1.24–4.22) where cases were more likely to be small for gestational age (χ2 = 7.66; p = 0.006). Cases also had a higher probability than controls of needing at least one specialist visit in a child neuropsychiatry outpatient service (OR: 1.74; 95% CI: 1.22–2.49).

Background and aims There are concerns that incretin-based antidiabetic drugs – including dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists – increase the risk of hospitalization for heart failure (HF). To further analyse this issue, we conducted a nested case-control study within a cohort of antidiabetic users in a real world setting. Methods and results Within a cohort of 133,639 subjects with a first prescription of an antidiabetic drug (new-users) between 2010 and 2016 in Lombardy, Italy, and were followed-up to 2016, we identified 4057 subjects with a first hospitalization for HF and 80,450 controls matched on sex, age, and date of cohort-entry. The multivariate odds ratios (ORs) of HF in relation to current use of incretin-based drugs as compared to current use of two or more oral antidiabetics was 1.06 (95% confidence interval, CI, 0.83–1.35), with no evidence of a trend in risk with increasing duration of use. The corresponding ORs were 1.10 (95% CI 0.85–1.41) for DPP-4 inhibitors and 0.84 (95% CI 0.48–1.47) for GLP-1 receptor agonists. Estimates were consistent in various sensitivity analyses. Conclusions This study indicates that incretin-based drugs are not associated with an increased risk of hospitalization for HF, thus providing further reassurance on the cardiovascular safety of these antidiabetic drugs in the clinical practice.

Objectives To estimate the rate of paediatric attendance at emergency departments (EDs) in the Lombardy Region, Italy, and to determine the factors contributing to different patterns of use. Methods: By analysing healthcare administrative databases, ED attendance by 1.6 million youths

Objective To validate a set of indicators for quality of diabetes care through their relationship with measurable clinical outcomes. Design A retrospective cohort study was carried out from 2010 to 2015. Setting Population-based study. Data were retrieved from healthcare utilization databases of three Italian regions (Lombardy, Emilia Romagna and Lazio) on the whole covering 20 million citizens. Participants The 77 285 individuals who were newly taken in care for diabetes during 2010 entered into the cohort. Interventions Exposure to selected clinical recommendations (i.e. periodic controls for glycated hemoglobin, lipid profile, urine albumin excretion, serum creatinine and dilated eye exams) was recorded. Main outcomes measures A composite outcome was employed taking into account hospitalizations for brief-term diabetes complications, uncontrolled diabetes, long-term vascular outcomes and no traumatic lower limb amputation. A multivariable proportional hazards model was fitted to estimate hazard ratio, and 95% confidence intervals (CI), for the exposure-outcome association. Results Among the newly taken in care patients with diabetes, those who adhered to almost none (0 or 1), just some (2 or 3) or almost all (4 or 5) recommendations during the first year after diagnosis were 44%, 36% and 20%, respectively. Compared patients who adhered to almost none recommendation, significant risk reductions of 16% (95% CI, 6–24%) and 20% (7–28%) were observed for those who adhered to just some and almost all recommendations, respectively. Conclusions Tight control of patients with diabetes through regular clinical examinations must to be considered the cornerstone of national guidance, national audits and quality improvement incentives schemes.

BACKGROUND. Statins, are to date the most effective drugs for the treatment of hypercholesterolemia, and their important protective role in the prevention of cardiovascular (CV) morbidity and mortality is well-established [1]. Since people aged between 60 and 79 years were well represented in many trials, this applies also to elderly patients [2]. However, it does not apply to patients aged 80 years or older, because (i) none or few octogenarians have been included in outcome-based trials and (ii) evidence on the protective effects of statins among them is limited to only few observational studies with inconsistent results [3,4]. This represents an important limitation because the increasing life expectancy makes octogenarians the fastest growing subgroup of the population and, furthermore, this highly advanced aged subgroup accounts for a considerable portion of the overall CV events, hospitalizations and deaths [5]. AIM. To assess whether in individuals aged 80 years or older adherence to statins is accompanied by a reduced risk of all-cause mortality and major cardiovascular events. METHODS. A nested case–control study was carried out including a cohort of patients aged 80 years or older, who were under treatment with statins between 2008 and 2009, using the administrative databases of Lombardy region (Italy). Cases were the cohort members who experienced death or hospitalization for stroke, myocardial infarction or heart failure from the initial prescription until 2012. Up to five controls were randomly selected for each case. Logistic regression was fitted to estimate the odds ratio (OR), and its 95% confidence interval (CI), for the considered outcomes in relation to the adherence to therapy with statins, measured by the proportion of days covered (PDC). Four categories of adherence were employed (i.e., =75%), using the lowest one (

Objective: Our objective was to assess the relationship between antihypertensive drugs, loop diuretics, and the risk of hospitalization for hip fracture (HF). Design: We conducted a population-based study in a cohort of 81,617 patients from Lombardy (Italy) aged 70–90years who were newly treated with antihypertensive agents or loop diuretics between 2005 and 2009. Cases were the 2153 patients who experienced the outcome (hospitalization for HF before 31 December 2012). For each case, up to three controls were randomly selected from the cohort to be matched for sex, age at cohort entry, and date of initial prescription. The case–control and case-crossover designs and the logistic regression for matched sets were used to measure the strength of the association between current use of an antihypertensive drug (within 30days before the HF hospitalization) and the risk of outcome. Results: Case–control and case-crossover odds ratios (ORs) for current use of loop diuretics were 1.67 (95% confidence interval [CI] 1.28–2.18) and 1.49 (95% CI 1.05–2.10), respectively. Among patients aged 81–90years, case–control and case-crossover ORs were 1.52 (95% CI 1.04–2.21) and 1.82 (95% CI 1.10–3.00) for current use of loop diuretics and 1.86 (95% CI 1.03–3.35) and 1.88 (95% CI 1.01–3.48) for α-blockers. No other agent was associated with the outcome. Conclusions: Evidence that loop diuretics and α-blockers are associated with a higher risk of HF was consistent in the two observational approaches. Clinicians should carefully consider the risk of falls in their selection of drugs for hypertension and in the clinical use of loop diuretics.

Diabetes mellitus (DM) and atrial fibrillation (AF) are worldwide public health challenges and major causes of death and cardiovascular events. The association between DM and AF is controversial in literature and data on outcomes of individuals with both diseases have not been evaluated in population studies. We tested the hypothesis that DM is independently associated to AF hospitalization and assessed the risk of stroke and mortality in people with both conditions.We conducted a population-based cohort-study of DM patients and their corresponding controls identified in a administrative health database of the Lombardy Region. Both cohorts were followed for nine years. A multivariable Cox proportional-hazards-regression model was used to estimate the hazard ratio (HR) for first hospitalization for AF and for clinical outcomes.Out of 9,061,258 residents, 285,428 (3.14%) DM subjects were identified, mean age 65.8±15 years, 49% were women. The cumulative incidence of AF in DM was 10.4% vs. 7.4% in non-DM. DM was a risk factor for AF (HR 1.32, 95% CI 1.30-1.34; p0.0001). Oral anticoagulants were prescribed in 34.8% of DM patients with AF. DM associated with AF, presented the highest HR for stroke: 2.63; 95% CI 2.47-2.80 and for total death, HR 2.41; 95% CI 2.36-2.47.In this population study, DM was an independent risk factor for AF hospitalization. DM patients with AF had the highest risk of stroke and total mortality. Early identification of AF and a structured plan to optimize the comprehensive management of DM and AF patients is mandatory.

To describe the incidence of ischemic stroke, short-term mortality, recurrences, and prescription patterns.Data from administrative health databases of the Lombardy Region from 2002 to 2010 (about 4 million people) were analyzed for stroke incidence and recurrence, mortality, and drug prescriptions after an ischemic stroke.A total of 43,352 patients with a first hospital admission for ischemic stroke were identified. During 8 years, stroke incidence decreased from 3.2 of 1000 to 2.4 of 1000 (P.001) in people aged 65-74 years, from 7.1 of 1000 to 5.3 of 1000 (P.001) at ages 75-84 years and from 11.9 of 1000 to 9.4 of 1000 (P.001) at age 85 years or older. Stroke recurrences dropped by 30% (from 10.0% to 7.0%, P.001) and 30-day mortality rate also decreased. Prescription trends showed linear increase in antiplatelets and lipid-lowering drugs, respectively, from 60.2% to 65.0% (P.001) and from 19.1% to 34.6% (P.001), whereas antihypertensive prescriptions did not change appreciably. Anticoagulant prescription increased in patients with atrial fibrillation, from 64.8% to 72.1% in the 65-74 years age group, (P = .004) and from 40.2% to 53.7% in the 75-84 years age group (P.001); less than 20% of the 85 years or older age group were treated with anticoagulants (P.0001).Stroke incidence, recurrence, and 30-day mortality decreased from 2002 to 2010 concomitant with an increase in prescriptions of secondary stroke prevention drugs.

Purpose Insulin and other antidiabetic drugs may modulate hepatocellular carcinoma (HCC) risk in diabetics. Methods We have analyzed the role of various antidiabetic drugs on HCC in a nested case-control study using the healthcare utilization databases of the Lombardy Region in Italy. This included 190 diabetic subjects with a hospital discharge reporting a diagnosis of malignant HCC and 3772 diabetic control subjects matched to each case on sex, age, date at cohort entry, and duration of follow-up. Results Increased risks of HCC were found for use of insulin (odds ratio [OR] = 3.73, 95% confidence interval [CI] 2.52–5.51), sulfonylureas (OR = 1.39, 95%CI 0.98–1.99), and repaglinide (OR = 2.12, 95%CI 1.38–3.26), while a reduced risk was found for use of metformin (OR = 0.57, 95%CI 0.41–0.79). The risk of HCC increased with increasing duration of insulin use (OR = 2.52 for

Networks are well suited to display and analyze complex systems that consist of numerous and interlinked elements. This study aimed at: (1) generating a series of drug prescription networks (DPNs) displaying co-prescription in community-dwelling elderly people; (2) analyzing DPN structure and organization; and (3) comparing various DPNs to unveil possible differences in drug co-prescription patterns across time and space. Data were extracted from the administrative prescription database of the Lombardy Region in northern Italy in 2000 and 2010. DPNs were generated, in which each node represents a drug chemical subclass, whereas each edge linking two nodes represents the co-prescription of the corresponding drugs to the same patient. At a global level, the DPN was a very dense and highly clustered network, whereas at the local level it was organized into anatomically homogeneous modules. In addition, the DPN was assortative by class, because similar nodes (representing drugs with the same anatomic, therapeutic, and pharmacologic annotation) connected to each other more frequently than expected, indicating that similar drugs are often co-prescribed. Finally, temporal changes in the co-prescription of specific drug sub-groups (for instance, proton pump inhibitors) translated into topological changes of the DPN and its modules. In conclusion, complementing more traditional pharmaco-epidemiology methods, the DPN-based method allows appreciatiation (and representation) of general trends in the co-prescription of a specific drug (e.g., its emergence as a heavily co-prescribed hub) in comparison with other drugs.

Objective Predictors of mortality and readmission among patients hospitalized for the first time for heart failure (HF) were investigated for a large, unselected population. Methods The cohort of 13,171 patients in the Lombardy Region (Italy), all of whom were aged 50years or older and survived their first hospitalization for HF during 2011, were followed after discharge. Mortality and readmission within 30days and one year of index discharge were investigated. Kaplan–Meier estimator and Cox model were respectively used to estimate the cumulative proportions of patients experiencing the outcomes and the hazard ratio (HR) for the association between selected covariates and time of outcome onset. Results Within 30days of index discharge, 4.7% and 4.3% of the cohort members died or were readmitted for HF, respectively, while 22.6% and 57.2% of them died or were readmitted for any cause within one year of index discharge. Older age was an independent predictor of mortality at both 30days and one year. One-year mortality was affected by the use of diuretics, mineralocorticoid receptor antagonists and antigout preparations and by previous hospitalization for respiratory and cerebrovascular diseases. Younger age, use of antidiabetics, diuretics, other antihypertensives, NSAIDs and antigout preparations and previous hospitalization for renal, respiratory, coronary heart and cerebrovascular disease, were independent predictors of hospital readmission. Conclusion Short- and long-term mortality and readmissions after first hospitalization for HF are high and heterogeneous across different patient subgroups. Characterization of hospitalized HF is very important in assisting clinicians in decision-making and targeting treatment of high-risk patients.

To compare the utilization of health care resources (drug prescriptions, hospital admissions and health care services) by immigrant versus native elderly people (65 years or more), by using administrative database of the Lombardy Region. For each immigrant (an older people born out of Italy), one person born in Lombardy (native) was randomly selected and matched by age, sex and general practitioner. The 25,508 immigrants selected were less prescribed with at least one drug (OR 0.72, 95 % CI 0.67-0.76) and had a lesser use of health care services (OR 0.79, 95 % CI 0.75-0.84) than natives. No statistically significant differences were found for hospital admission rates (OR 0.99, 95 % CI 0.99-1.04). A lower rate of health care resource utilization was observed in elderly immigrants who had been living in the host region for as many as 10 years.

To describe the prevalence and management of diabetes among immigrants according to ethnic group and duration of stay, compared to Italian citizens. Diabetic immigrant and Italian residents aged 20–69 years in the administrative database of the Lombardy Region. Immigrants were classified by region of origin and as long-term residents (LTR) and short-term residents (STR). Age- and sex-adjusted prevalence and indicators of diabetes management were calculated for immigrants by region of origin and by length of stay using Cox proportional models. In 2010 19,992 immigrants (mean age 49.1 ± 10.8, 53.7% males) and 195,049 Italians (mean age 58.7 ± 9.3, 61.1 males) with diabetes were identified. Immigrants had a higher adjusted diabetes prevalence than Italians (OR 1.48; 95% CI 1.45–1.50). STR received significantly fewer recommended cardiovascular drugs (antiplatelets, statins and ACE-inhibitors/ARBs) than Italians, although prescription was higher among LTR from some ethnic groups. Immigrants were less likely to be seen by a diabetologist and to do at least one HbA1c test per year. Although the recommended tests/visits were more often done for the LTR than the STR, in the majority of ethnic groups these indicators were still far from optimal. The prevalence and management of diabetes differ between immigrants and Italians, although some improvement can be seen among LTR.

Background Maternal socioeconomic disparities strongly affect child health, particularly in low and middle income countries. We assessed whether neonatal outcomes varied by maternal education in a setting where healthcare system provides universal coverage of health services to all women, irrespective of their socioeconomic status. Methods A population-based study was performed on 383,103 singleton live births occurring from 2005 to 2010 in Lombardy, an Italian region with approximately 10 million inhabitants. The association between maternal education, birthplace and selected neonatal outcomes (preterm birth, low birth weight, small-for-gestational age, low 5-min Apgar score, severe congenital anomalies, cerebral distress and respiratory distress) was estimated by fitting logistic regression models. Model adjustments were applied for sociodemographic, reproductive and medical maternal traits. Results Compared with low-level educated mothers, those with high education had reduced odds of preterm birth (Odds Ratio; OR = 0.81, 95% CI 0.77–0.85), low birth weight (OR = 0.78, 95% CI 0.70–0.81), small for gestational age (OR = 0.82, 95% CI 0.79–0.85), and respiratory distress (OR = 0.84, 95% CI 0.80–0.88). Mothers born in a foreign country had higher odds of preterm birth (OR = 1.16, 95% CI 1.11–1.20), low Apgar score (OR = 1.18, 95% CI 1.07–1.30) and respiratory distress (OR = 1.19, 95% CI 1.15–1.24) than Italian-born mothers. The influence of maternal education on neonatal outcomes was confirmed among both, Italian-born and foreign-born mothers. Conclusions Low levels of education and maternal birthplace are important factors associated with adverse neonatal outcomes in Italy. Future studies are encouraged to investigate factors mediating the effects of socioeconomic inequality for identifying the main target groups for interventions. Electronic supplementary material The online version of this article (doi:10.1186/s12884-017-1418-1) contains supplementary material, which is available to authorized users.

To evaluate the association between diabetes mellitus (DM) and risk of seizures in a well-defined elderly population. The administrative databases of the Lombardy region (a 10 million population area in Northern Italy) were used to identify persons aged 65 years or older with DM (defined by prescription of antidiabetic drugs and/or through ICD-9 CM code and/or exemption code for diabetes) during the year 2002. Seizure-free DM subjects were followed until 2012 in search of individuals with incident seizures (identified through ICD-9 CM codes for epilepsy/seizures or ATC codes for antiepileptic drugs associated with the prescription of an electroencephalogram). To adjust for confounding, comorbidities having epileptogenic potential were also identified through the ICD-9 CM codes. The population at risk included 1,494,071 persons. Of these, 136,941 seizure-free patients had DM. At the end of follow-up, the cumulative time-dependent incidence of seizures was 3.0% in DM patients and 1.9% in No-diabetic individuals (hazard ratio, HR 1.47; 95% confidence interval, 1.41–1.53, adjusted for age classes, sex, comorbidities and number of hospital admission). The HR was unchanged in patients with no history of stroke. The cumulative incidence of seizures after DM increased with the number of hospital admissions. DM is an independent risk factor for seizures in elderly individuals. In diabetic patients, the risk of seizures increases with the number of comorbidities, supporting the role of vascular disease as a cause of seizures.

Objective To assess whether in individuals aged 85 years or older, adherence to antihypertensive drugs is accompanied by a reduced risk of cardiovascular events. Methods A nested case-control study was carried out on a cohort of patients aged 85 years or older, who were newly treated with antihypertensive drugs between 2007 and 2009, using the database available for all citizens (about 10 million) of Lombardy (Italy). Cases were the cohort members who experienced death or hospital discharge for stroke, myocardial infarction (MI) or heart failure from the initial prescription until 2012. Up to five controls were randomly selected for each case. Logistic regression was used to model the outcome risk associated with the adherence with antihypertensive drug therapy. A patient cohort aged 70-84 years was taken for comparison. Results Compared with patients with very low adherence, those aged 85 years or older (average 88 years) with high adherence showed a risk reduction for death (47%; 95% confidence interval, 5-57%) and all the outcomes combined (34%; 95% confidence interval, 21-45%). The risk of heart failure and stroke was also reduced, whereas the risk of MI was not affected by adherence with antihypertensive drugs. Similar findings were obtained in the cohort of patients aged 70-84 years. Conclusion Adherence with antihypertensive drug therapy reduced the risk of cardiovascular morbidity in patients aged 85 years or more, the benefit including heart failure and stroke, although not MI, and extending to all-cause death.

Introduction. A large number of studies has shown that use of statins is accompanied by an increased risk of developing type 2 diabetes [1-5], which is thus currently listed as an inconvenience of these drugs that may attenuate in some patients their protective effect. However, several aspects of the statin-induced diabetes have not been adequately clarified. For example, albeit several hypotheses have been advanced, the mechanisms through which statins favour the alteration of glucose metabolism that leads to the appearance of hyperglycemia and diabetes remain unclear [4,6]. Furthermore, although statin-induced diabetes is generally believed not to offset the protective lipid-lowering effect of statins on the cardiovascular (CV) system [7-9], limited information exists on whether statin-induced diabetes has the same adverse prognostic significance of native diabetes, i.e., whether it is associated with a similar increasing risk of diabetes-related macrovascular complications. This information is of fundamental importance to reliably quantify the impact of statin-induced diabetes on the role played by statins on primary and secondary CV prevention [10,11]. Aims. Since we have previously shown that at the population level an increasing adherence with statin treatment is accompanied by a clear-cut progressive increase in the risk of new onset type 2 diabetes [12], thus the purpose of the present study was to provide information on the extent to which type 2 diabetes more likely induced by statins affects the risk of macrovascular complications to a similar or different degree compared to diabetes of a more likely native nature. Methods. The data used for this study were retrieved from the healthcare utilization databases of Lombardy, a Region of Italy which accounts for about 16% (almost ten million) of its population, by means of a record-linkage procedure among databases. In Italy, the whole population is covered by the National Health Service and in Lombardy this has been associated since 1997 with an automated system of databases to collect a variety of information. All the residents in Lombardy, with an age between 40 and 80 years and at least one prescription of statins between 2003 and 2005, were identified. The date of the first dispensation was considered as the step-1 index date. Four patient categories were excluded: (i) patients who received one or more statin prescriptions within three years prior the step-1 index date; (ii) patients who received at least one antidiabetic agent, or were hospitalized with a diagnosis of diabetes, within the three years before the step-1 index date; (iii) patients who were hospitalized for CV disease or received prescriptions of CV drugs such as nitrates or digitalis within the three years before the step-1 index date; and (iv) patients who did not renew the initial prescription of statins and/or did not reach at least one year of follow-up. The remaining 84,828 patients newly treated with statins between 2003 and 2005 were enrolled in the study and represented the step-1 cohort, each of its members accumulating person-years of follow-up from the step-1 index date (i.e., index statin prescription) until the earliest among the dates of starting antidiabetic drug therapy (step-1 outcome, i.e., the appearance of diabetes as diagnosed by the prescription of antidiabetic drugs) or censoring, e.g. death from any cause, emigration or step-1 phase stopping (i.e., December 31th 2009). The 4,391 step-1 cohort members who exhibited new onset diabetes and the 77,893 statin-treated patients who did not have any antidiabetic drug dispensation were considered eligible for inclusion in the step-2 cohort. Cohort members who experienced diabetes were 1:1 randomly matched with those who did not developed diabetes for gender, age at cohort entry (±1 year), step-1 index date (±30 days) and previous adherence with statin therapy. A patient without diabetes had also to be at risk of developing diabetes when this was identified in the matched patient with diabetes. The 1,070 couples (formed by a patient with diabetes and his/her match without diabetes) who experienced a hospitalization for CV disease during the step-1 follow-up were excluded. The remaining 3,321 diabetic and non-diabetic matched pairs represented the step-2 cohort, each of its members accumulating personyears of follow-up from the date of the first antidiabetic drug prescription (i.e., the step-2 index date), until the earliest among the dates of step-2 outcome (first admission to public or private hospitals for macrovascular complications), death from any cause, emigration, or December 31th 2012. Macrovascular complications included myocardial infarction, peripheral vascular disease, myocardial revascularization, heart failure and cerebrovascular disease, as reported by the diagnosis at discharge from hospital. All prescriptions of statins dispensed to the cohort members during the step-1 follow-up were identified. Adherence with therapy was quantified as the cumulative number of days during which the medication was available divided by the number of days of follow-up, i.e., the “proportion of days covered” (PDC) by treatment. A two-stage data analysis was carried out. In the first stage, we looked for replication of our previous findings [12] that increasing the level of adherence with statins increases the risk of developing diabetes (the step-1 outcome), using the step-1 cohort. Cox proportional hazard regression was used to estimate the hazard ratio (HR), and the 95% CI, for patients to develop diabetes in relation to the exposure to statin treatment. The exposure to statin treatment was quantified by four PDC categories, i.e. a very low (PDC < 10%), low (PDC from 11% to 50%), intermediate (PDC from 51% to 89%) and high (PDC ≥ 90%) adherence with statins. Because drug exposure may vary over time, adherence categories were included in the model as time-dependent variables, thereby accounting for their cumulative and varying nature. Data were also adjusted for 1) the type of the index prescribed statin; 2) previous use of antihypertensive, antiarrhythmic, antithrombotic and antidepressant agents, as well as of no-steroidal anti-inflammatory drugs and drugs used for chronic obstructive lung disease; and 3) the Charlson comorbidity index score, calculated in the three years prior the step-1 index date. The second-stage data analysis focused on whether the greater or lesser chance for diabetes to be induced by statins translated into a different risk of macrovascular complications. To this aim, the 3,321 matched pairs forming the step-2 cohort were stratified according to the four categories of adherence with statins used for the step-1 follow-up. The overall risk of macrovascular complications associated with the diabetic condition was calculated for the entire cohort, as well as separately in each category of adherence with statins, using the HR, and 95% CI, derived from the Cox proportional hazard model. The risk of each specific macrovascular complication was also. Data were adjusted for the aforementioned covariates (excluding matching variables) as time-fixed. At the step-2 index date, covariates also included adherence with statins during the step-1 follow-up as well as with antidiabetic agents during the step-2 follow-up. Two ancillary analyses were performed to check whether interpretation of the risk of macrovascular complications in diabetic patients with a different adherence to statin might be affected by (i) a delayed protective effect of statin dispensed during the step-1 follow-up and/or (ii) the exclusion of patients with CV events during the step-1 follow-up or before the inclusion in the study, with thus a selection of those less susceptible to the protective effect of the drug. The Statistical Analysis System Software (version 9.4; SAS Institute, Cary, North Carolina, USA) was used for the analyses. For all hypotheses tested, two-tailed p-values less than 0.05 were considered to be significant. Results. The 84,828 patients belonging to the step-1 cohort accumulated 467,317 person-years of follow-up, on average 5.5 years per patient. During this period, 6,935 patients started antidiabetic therapy (the step-1 outcome) with an incidence of 14.8 cases every 1,000 person-years. The risk of developing diabetes raised progressively and significantly as adherence with statin increased. Compared to patients with very low adherence, the increase was 24% (95% CI: 12% to 37%), 72% (95% CI: 56% to 90%), and 95% (95% CI: 60% to 139%) for patients with low, intermediate and high adherence, respectively. The 3,321 matched pairs of diabetic and non-diabetic patients belonging to the step-2 cohort accumulated 33,623 person-years of follow-up, on average 5.0 years per patient. During this period, 376 and 272 diabetic and non-diabetic patients respectively experienced the step-2 outcome, the corresponding incidence being 22.9 and 16.1 hospitalizations every 1,000 person-years. The diabetes - macrovascular disease association experienced during the step-2 follow-up from the entire cohort of diabetic and non-diabetic patients, as well as within each category of step-1 adherence with statins, is shown in Figure 1. In the entire cohort, patients with diabetes had a risk excess of macrovascular complications 35% (15% to 58%) higher than that of patients without diabetes. As shown in the top panel of Figure 1, the potential of diabetes for generating macrovascular complications decreased with the increasing adherence to statins, the risk excess being 88% (95% CI: 17% to 204%), 51% (18% to 94%), 16% (-8% to 46%) and 4% (-64% to 197%) for very low, low, intermediate and high adherence, respectively. P-value for heterogeneity (p-value=0.0217) raises the significance. This trend was similar for the specific events separately considered, for all of which the diabetes-related risk was much less in patients with a high as compared to low adherence: 111% vs 9% for myocardial infarction, 112% vs 16% for myocardial revascularization and 59% vs 8% for cerebrovascular disease (Figure 1, bottom panel). The results of the ancillary analysis further confirmed the results obtained. Conclusions. In summary, our data confirm that there is a definite increase in the development of diabetes with statin therapy (as observed during the step-1 follow-up). Type 2 diabetes lost its association with increasing macrovascular risk when previous adherence with statin treatment was very high, and thus the chance of its induction by the drug greater. Statin-dependent type 2 diabetes might be prognostically less adverse than native diabetes.Trials reflecting the clinical relevance of treatment-induced diabetes mellitus compared to naïve diabetes mellitus regarding macrovascular complications are required to confirm this finding

The aims of this study are to analyse, in community-dwelling people aged 65+ living in Italy’s Lombardy Region, electrocardiographic (ECG) monitoring for new users of the atypical antipsychotic quetiapine co-prescribed with acetylcholinesterase inhibitors (AChEIs) or memantine and to find independent predictors of ECG monitoring before and after the starting of this prescription. The Lombardy Region’s administrative health database was used to retrieve prescriptions of ECG exams as well as prevalence rates of subjects aged 65+ who were prescribed such psychotropic drugs from 2005 to 2009. Multivariable analyses were adjusted for age, sex, number of drugs, treatment with beta-blockers, digoxin, verapamil or diltiazem, any antiarrhythmic drug and antidepressants. Overall 2,623 community-dwelling older people started therapy with quetiapine, co-prescribed with AChEIs or memantine, during these 5 years. At least one ECG was performed in 714 cases (27.2 %) in the 6 months before—and in 398 cases (15.2 %) within 3 months after—the starting of this prescription. ECG monitoring was performed both before and after starting quetiapine in only 160 cases (6.1 %). At multivariable analyses, number of drugs taken, beta-blocker and antiarrhythmic drug use were found to be independent correlates of ECG monitoring whereas female sex was associated with a lower probability of receiving an ECG within 3 months after the initiation of quetiapine (odds ratio 0.78, 95 % CI 0.62–0.98). ECG monitoring for new prescriptions of quetiapine in older people suffering from behavioural and psychological symptoms in dementia was actually performed infrequently, independently of the age of drug users, especially in women. Our results support the need for greater awareness within the medical community of the importance of such ECG monitoring.

The aim of this study was to assess recent trends in hospital mortality and in the treatment techniques for patients with ST-segment elevation myocardial infarction according to gender. Data on hospitalizations for ST-segment elevation myocardial infarction from 2000 to 2010 were extracted from hospital discharge record databases (International Classification of Diseases, Ninth Revision, Clinical Modification, codes) in the Lombardy Region of Italy. The impact of female gender on in-hospital mortality was assessed by multivariable regression after adjusting for invasive approach use (i.e., coronary angiography, angioplasty or coronary artery bypass graft), age, and co-morbidities. A total of 89,562 patients, men (66.5%) and women (33.5%), were enrolled. The use of an invasive approach increased over time in both sexes although it was higher in men (from 54.9% in 2000 to 91.9% in 2010 in men; from 36.8% in 2000 to 72.0% in 2010 in women). This pattern was driven by the subgroup of patients aged ≥75 years, whereas differences between sexes were not observed in patients65 years and were small in patients aged 65 to 74 years. In-hospital mortality presented a small decrease from 7.6% in 2000 to 6.2% in 2010 in men (p for trend = 0.004), whereas it remained higher and substantially constant over time in women (16.6% in 2000, 15.5% in 2010, p for trend = 0.09). At multivariable regression, female gender did not emerge as an independent predictor of mortality (p = 0.13). However, a significant gender-age interaction was found, with female gender being a significant predictor of increased mortality in patients aged ≥75 years (odds ratio [OR] 1.33) while predicting a reduced mortality in patients aged75 years (OR 0.93, p for interaction0.0001). The use of an invasive approach was an independent predictor of mortality (OR 0.23, p0.0001), the magnitude of mortality reduction being higher in men than in women and in patients aged75 years than in those aged ≥75 years. In conclusion, a weak temporal trend in mortality reduction is observed in men only, which is driven by patients aged ≥75 years. In-hospital mortality remains higher in women than in men, although female gender is not a significant predictor of mortality. Despite temporal increases in the use of an invasive approach, women are more often treated conservatively.

OBJECTIVES:: We have previously shown that in Italian region of Lombardy (about 10 million citizens), adherence to antihypertensive treatment is low, and that this is associated with a greater risk of hospitalization for cardiovascular events. In this study, we used a healthcare database to study the factors involved in discontinuation of antihypertensive drug prescriptions in real life. METHODS AND RESULTS:: The analysis was restricted to 493 623 new users of antihypertensive drugs (no prescriptions in the previous 3 years) recruited in 2003, 2006 and 2009. Discontinuation was defined as lack of prescription renewal for at least 3 months. Each patient was followed at most for 1 year. The adjusted risk of treatment discontinuation depended on the type of initial antihypertensive treatment (diuretic monotherapy associated with higher risk) and it was lower in men (-17%) and older (-21 to -29%) patients, in patients with co-treatment with antidiabetic drugs, or hospitalization for cardiovascular or renal disease (-12 to -27%), but greater in patients under co-treatment with antidepressant drugs or hospitalization for concomitant pulmonary, rheumatic, neoplastic or neurological diseases (+9 to +32%). An unexpected relationship between discontinuation of treatment and density of the population of patient's residence, with a much greater discontinuation in metropolitan areas, was observed. CONCLUSIONS:: In a real life setting, discontinuation of antihypertensive treatment is affected in an opposite direction by a large number of factors: type of antihypertensive treatment, co-treatments, clinical conditions and even demographic characteristics of the geographical area where the patient lives. Knowledge of these factors may help the effort to reduce this phenomenon.

OBJECTIVE To investigate the relationship between adherence with statin therapy and the risk of developing diabetes. RESEARCH DESIGN AND METHODS The cohort comprised 115,709 residents of the Italian Lombardy region who were newly treated with statins during 2003 and 2004. Patients were followed from the index prescription until 2010. During this period, patients who began therapy with an antidiabetic agent or were hospitalized for a main diagnosis of type 2 diabetes were identified (outcome). Adherence was measured by the proportion of days covered (PDC) with statins (exposure). A proportional hazards model was fitted to estimate hazard ratios (HRs) and 95% CIs 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 follow-up, 11,154 cohort members experienced the outcome. Compared with patients with very-low adherence (PDC CONCLUSIONS In a real-world setting, the risk of new-onset diabetes rises as adherence with statin therapy increases. Benefits of statins in reducing cardiovascular events clearly overwhelm the diabetes risk.

To describe prescribing patterns in elderly Italian diabetic patients of the Lombardy Region in 2000 and 2010 using an administrative database. Hospital admissions and mortality were also recorded and compared in the two index years.Analyses were performed on the whole cohort of elderly diabetic patients and across age groups. Direct age standardization was done, with data from the Lombardy Region database for 2005 used as reference to compare diabetic populations in the two index years. Logistic regression models were used to analyze changes in hospital admissions and mortality and to calculate odds ratios.Using data retrieved from the Lombardy Region database we identified 176,384 and 283,982 elderly diabetic patients in 2000 and 2010, respectively. The overall rates of patients treated with antidiabetic drugs were 92.5% in 2000 and 97.0% in 2010. Between 2000 and 2010 the prescribing of glibenclamide declined by 30.0% (from 52.9 to 22.9%, p 0.001) and that of biguanides rose by 17.4 % (from 47.5 to 64.8%, p 0.001). In 2010 thiazolidinediones, dipeptidyl peptidase-4 inhibitors and incretin mimetic drugs were seldom prescribed. Drugs for cardiovascular prevention rose in all age classes from 2000 to 2010, and the rates of hospital admission overall fell from 32.0 to 26.8% (p 0.001) during the same period, with the exception of those aged ≥85 years. Between 2000 and 2010 the mortality rate decreased in patients aged 65-74 years (from 3.4 to 2.9%, p 0.0001) and rose significantly in those aged ≥85 years.The drug prescription profile of elderly diabetic patients changed from 2000 to 2010, with a tendency toward recommended drugs. These changes may possibly be linked to the decrease in both hospital admissions and mortality in the diabetic group aged 65-74 years.

Aims Heart failure has been described as one of the emerging pandemics of the 21st century. This report aims to measure the burden of new hospitalization for heart failure in the population of an Italian region of nearly 10 million inhabitants. Methods and results Data were retrieved from healthcare utilization databases covering the population of the Italian region of Lombardy. We identified patients who were hospitalized for the first time with a primary diagnosis of heart failure (hospitalized heart failure, HHF) during 2011. Incident HHF cases were used for measuring incidence rates and exploring mortality, re-hospitalizations, and healthcare costs on the 1-year time horizon after the index hospitalization. Out-of-hospital mortality, hospitalizations, and healthcare costs were also measured in a referent cohort free from heart failure hospitalization and matched 1:1 by gender and age with the HHF cohort. The overall HHF incidence rate was 32 and 20 events per 10 000 person-years in men and women, respectively. The incidence increased steeply with age in both genders. Among newly hospitalized patients, 7% died during hospitalization. Among survivors, cumulative out-of-hospital mortality and hospital readmission were 24% and 59%, respectively. The average per capita cost was €11 000, the main cost being hospitalizations. Mortality, readmissions, and costs experienced by HHF patients of 88, 75, and 79%, respectively, exceeded those of the referent cohort. Conclusions The main burden associated with HHF is related to hospitalizations. Effective treatment options that decrease hospitalization rates could reduce patients' suffering and offer considerable cost savings.

Because of their lower cost, healthcare systems recommend physicians to prefer generic products, rather than brand-name medicaments. There is then considerable interest and debate concerning safety and effectiveness of generic products. Few studies have compared patients treated with brand-name and generic drugs for adherence to treatment, with somewhat inconsistent results. The primary objective of this study was to compare the risk of discontinuing antihypertensive drug therapy in patients treated with generic or brand-name agents.The 101,618 beneficiaries of the Healthcare system of Lombardy, Italy, aged 18 years or older who were newly treated on monotherapy with antihypertensive generic or brand-name drugs during 2008, were followed until the earliest date among those of the occurrence of treatment discontinuation to whatever antihypertensive drug therapy (outcome), or censoring (death, emigration, 12 months after treatment initiation). Hazard ratios of discontinuation associated with starting on generic or brand-name products (intention-to-treat analysis), and incidence rate ratio of discontinuation during periods on generic and brand-name products (as-treated analysis) were respectively estimated from a cohort and self-controlled case series analyses.Patients who started on generics did not experience a different risk of discontinuation compared with those starting on brand-name agents (hazard ratio: 1.00; 95% confidence interval 0.98-1.02). Discontinuation did not occur with different rates during periods covered by generics or brand-name agents (incidence rate ratio: 1.01; 95% confidence interval 0.96-1.11) within the same individuals. A number of sensitivity and subgroup analyses confirmed the robustness of these findings.Generic products are not responsible for the high rate of discontinuation from antihypertensive drug therapy. Assuming therapeutic equivalence, clinical implication is of prescribing generic drug therapies.

To investigate the changes in the last decade (2000–2010) in drug prescribing among community-dwelling elderly people aged 65–94 years, in relation to age and sex. We analyzed the data of nearly two million subjects ranging in age from 65 to 94 years recorded in the Drug Administrative Database of the Lombardy Region (Italy) from 2000 to 2010. Associations between drug use (at least one drug, one chronic drug, polypharmacy or chronic polypharmacy) and age, sex, and year of prescription were analyzed by logistic regression analysis. We also analyzed differences in changes linked to sex and age. Between 2000 and 2010, the prescriptions of at least one drug or one chronic drug increased by 2 % (from 88.0 to 90.3 %; p

Meta-analyses have found conflicting evidence on the link between antipsychotics and cerebrovascular events (CVEs). The primary aim of this study was to evaluate the association between any antipsychotic prescription and CVEs in Italian elderly; second, to compare the effect of typical and atypical antipsychotics on CVEs; and third, to investigate the effect of antipsychotics on CVEs in the subgroup of persons coprescribed with acetylcholinesterase inhibitors (AChEIs). Administrative claims from community-dwelling people aged 65 to 94 years living in Northern Italy were analyzed using a retrospective case-control design, from 2003 to 2005. The primary outcome measure was a hospital discharge diagnosis of CVEs during 2005. Four age-, sex-, and local health unit-matched control subjects were identified for each case. Antihypertensive drugs, anticoagulants, platelet inhibitors, antidiabetic drugs, lipid-lowering drugs, and AChEI were used as covariates in conditional logistic regression models testing the odds ratio (OR) for CVEs due to antipsychotics use. Three thousand eight hundred fifty-five cases of CVEs were identified and matched with 15,420 control subjects. In multiadjusted models, the association of any antipsychotics, typical or atypical with CVEs, was not significant. When antipsychotics were categorized according to the number of boxes prescribed during the observational period, being prescribed with at least 19 boxes of typical antipsychotics was significantly associated with CVEs (OR, 2.4; 95% confidence interval, 1.08-5.5). An interaction was found between any antipsychotic and AChEI coprescription on CVEs (OR, 0.46; 95% confidence interval, 0.23-0.92). In conclusion, only typical antipsychotics were associated with an increased odd of CVEs, but the association was duration dependent. Persons prescribed simultaneously with AChEI and antipsychotics may be at a lower risk of CVEs.

Metformin may reduce the risk of endometrial cancer whereas other drugs for the treatment of type 2 diabetes mellitus appear to increase it, although the evidence is still limited. We investigated this issue using data from a nested case-control study within the healthcare utilization databases of the Lombardy Region, Italy. This study included 376 diabetic women with endometrial cancer and 7485 diabetic controls matched for cases on age, date at cohort entry, and duration of follow-up. We used conditional logistic regression models to estimate the odds ratio (OR) of endometrial cancer in relation to use of antidiabetic drugs, adjusted for the Charlson's comorbidity index, selected medical conditions, prescription of selected drugs, and concomitant use of other antidiabetic drugs. At cohort entry, no significant associations were observed for metformin [OR=0.99, 95% confidence interval (CI) 0.80-1.23], sulfonylureas (OR=1.14, 95% CI 0.91-1.42), insulin (OR=0.72, 95% CI 0.34-1.56), and other antidiabetic drugs (OR=1.21, 95% CI 0.75-1.95). When we considered use during follow-up, a borderline significant excess risk was found for metformin (OR=1.30, 95% CI 1.00-1.70). However, this estimate decreased to 1.07 (95% CI 0.82-1.41) when taking into account BMI using a Monte Carlo sensitivity analysis. No significant associations were found for sulfonylureas (OR=1.16, 95% CI 0.91-1.47), thiazolidinediones (OR=0.77, 95% CI 0.48-1.24), repaglinide (OR=1.32, 95% CI 0.94-1.87), incretins (OR=1.21, 95% CI 0.63-2.32), and insulin (OR=1.19, 95% CI 0.82-1.71). Our data indicate that metformin, insulin, and other antidiabetic drugs did not meaningfully affect the risk of endometrial cancer.

BACKGROUND AND AIMS: In contrast to the well-documented global prevalence of diabetes, much less is known about the epidemiology of cardiovascular (CV) complications in recent years. We describe the incidence of major CV events, deaths and drug prescribing patterns from 2002 to 2012 in subjects with (DM) or without diabetes mellitus (No DM). METHODS AND RESULTS: Subjects and outcomes were identified using linkable health administrative databases of Lombardy, a region in Northern Italy. A logistic regression model was used to compare myocardial infarction (MI), stroke, major amputation and death between DM and No DM in 2002 and 2012 and between the two index years in each population. The interaction between years and diabetes was introduced in the model. From 2002 to 2012 the incidence of major CV complications and death fell in both groups with a larger reduction among DM only for CV events: OR (95% CI) for the interaction 0.86 (0.79-0.93) for MI, 0.89 (0.82-0.96) for stroke, 0.78 (0.57-1.06) for major amputations. CV prevention drugs rose considerably from 2002 to 2012 particularly in DM and a switch towards safer antihyperglycemic drugs was also observed. CONCLUSIONS: Major CV complications and death declined from 2002 to 2012 in both DM and No DM. This might be due to a larger increase in prescriptions of CV drugs in DM and a relevant change toward recommended antihyperglycemic drugs. Background and aims In contrast to the well-documented global prevalence of diabetes, much less is known about the epidemiology of cardiovascular (CV) complications in recent years. We describe the incidence of major CV events, deaths and drug prescribing patterns from 2002 to 2012 in subjects with (DM) or without diabetes mellitus (No DM). Methods and results Subjects and outcomes were identified using linkable health administrative databases of Lombardy, a region in Northern Italy. A logistic regression model was used to compare myocardial infarction (MI), stroke, major amputation and death between DM and No DM in 2002 and 2012 and between the two index years in each population. The interaction between years and diabetes was introduced in the model. From 2002 to 2012 the incidence of major CV complications and death fell in both groups with a larger reduction among DM only for CV events: OR (95% CI) for the interaction 0.86 (0.79–0.93) for MI, 0.89 (0.82–0.96) for stroke, 0.78 (0.57–1.06) for major amputations. CV prevention drugs rose considerably from 2002 to 2012 particularly in DM and a switch towards safer antihyperglycemic drugs was also observed. Conclusions Major CV complications and death declined from 2002 to 2012 in both DM and No DM. This might be due to a larger increase in prescriptions of CV drugs in DM and a relevant change toward recommended antihyperglycemic drugs.

Incidence, predictors and effect of discontinuation of long-acting bronchodilators on the risk of death or hospital admission among adults with Chronic Obstructive Pulmonary Disease (COPD) were assessed in a large population-based prospective study carried out by linking Italian healthcare utilization databases. Specifically, the cohort of 17,490 beneficiaries of the National Health Service in the Italian Region of Lombardy, aged 40 years or older, who started long-acting bronchodilators therapy during 2005–2008 was followed from first dispensation until 2012. During this period, patients who experienced discontinuation of long-acting bronchodilators were identified. Hospitalizations for COPD and deaths for any cause (composite clinical outcome) were also identified during follow-up. A Cox proportional hazards model was fitted to identify predictors of discontinuation. The case-crossover design was used to assess the implications of treatment discontinuation on the clinical outcome risk. Cumulative incidences of discontinuation were, respectively, 67%, 80%, and 92% at 6 months, 1 year, and 5 years since initial treatment. Significant predictors of discontinuation were female gender, younger age, starting treatment with fixed-dose combination of inhaled bronchodilators and corticosteroids, using antibiotics, inhaled long-acting bronchodilators and corticosteroids and not using short-acting bronchodilators, other respiratory drugs and systemic corticosteroids during follow-up. Odds ratios (95% confidence intervals) for the clinical outcome associated with not discontinuing long-acting bronchodilators was 0.64 (0.50 to 0.82). In conclusion, in the real-life setting, discontinuation of inhaled long-acting bronchodilators in adults with COPD is high even after just 6 months, even though persistence to these drugs reduces the risk of severe outcomes.

To investigate the association between angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptors blockers (ARBs) and motor neuron disease (MND).This is a population-based nested case-control study. Data were obtained from a population registry and the administrative database of the Lombardy Region (Northern Italy) from 2000 through 2010. Included were 1,200 patients with newly diagnosed MND/ALS and 120,000 controls, randomly selected from the same population and matched for gender, age and area of residence. Exposure to ACEIs or ARBs was quantified using defined daily doses (DDDs). Cumulative DDD (cDDD) was estimated as the sum of dispensed DDDs in the preceding 5 years, excluding 1 year before the MND/ALS diagnosis. Overall exposure, levels of exposure, and individual drugs were all assessed. Subgroup analyses were performed according to age, sex, ALS and ACEI-ARB association.There was no significant association between MND/ALS and antecedent use of ACEIs or ARBs. Data were confirmed in multivariable models and in subgroups.A protective role of ACEIs and ARBs in MND was not confirmed. Differences with a previous report (showing an inverse association between ACEIs and ALS) can be explained by different genetic background, dietary habits and susceptibility to environmental exposures, including drugs.

The scope of this paper is to describe, within the complex national and regional legal context with respect to Open Data, the methodologies and opportunities for the use of such data in the health context in the Lombardy Region.

Background: Hip fracture (HF) is increasingly frequent with advancing age. Studies describing the HF incidence rate and survival after surgery in centenarians are scanty. To fill this gap, we performed a large population-based investigation on Lombardy centenarians (Italy). Methods: Retrospective observational cohort study based on information from the Healthcare Utilization Database. Among the cohort of 7,830 residents that reached 100 years of age between 2004 and 2011, incidence rate of HF was calculated. Two hundred fifty-nine patients were discharged alive from a hospital after HF and surgical repair (HF cohort). For each HF cohort member, a control was randomly selected from the initial cohort to be matched for gender and date of birth, and who did not experience HF from the date of their hundredth birthday until the date of hospital discharge of the corresponding HF cohort member. The survival curves and the hazard functions of HF and control cohort were calculated within 2 years. Results: Over a mean follow-up of 1.85 years, HF incidence rate was 23.1 per 1,000 centenarians per year. Survival probability was significantly lower in HF cohort than in control cohort (31.5 vs 48.1%, p

Background Previous studies have stated that atrial fibrillation (AF) is associated with a higher risk of dementia. However, none have examined the competition between death and incident dementia in patients with AF. We evaluated the risk of incident dementia in patients with AF in comparison to people without this arrhythmia, considering of the competing risk of death. Methods AF and non-AF cohorts were identified using the large administrative database of the Lombardy Region and followed for ten years. Patients with incident dementia were identified if they had an ICD 9 code referring to dementia at hospital discharge or a prescription for any anti-dementia drug. The association of AF with dementia or death was assessed with the multivariable Cox proportional-regression model, sensitivity analysis with a 1:1 propensity score matching and competing-risk analysis. Results In 2003 a total of 27,431 patients were hospitalized for AF in the Lombardy Region, while the cohort of non-AF counted 1,600,200 people. AF was associated with a higher risk of dementia (17%) and death (51%) at multivariable Cox analysis. These results were confirmed by the model fitted after propensity score matching. However, competing risk analysis found the association between AF and incident dementia was no longer significant (HR 0.99; 95% CI 0.94–1.04). Conclusions In this real-world population the association between AF and dementia was no longer statistically significant when death was considered a competing risk.

Background Untreated depression during pregnancy increases the risk of morbidity and mortality in the mother and child. Therefore, specific treatments are required for this population. Objective The study aimed to investigating the effect of antidepressant medication used during pregnancy with reference to the risk of preterm birth (PTB) and low birth weight (LBW). Methods A population-based study was carried out with data provided by the healthcare utilization database of Lombardy, an Italian region with about ten million inhabitants. The study included 384,673 births from 2005 to 2010. Maternal use of antidepressants before and during pregnancy was investigated. Log-binomial regression was used to estimate the association between the use of antidepressants during pregnancy, compared to the non-use or use just before pregnancy, and the prevalence ratio of PTB and LBW. Results Women who used antidepressants during pregnancy had a 20% (95% CI: 10–40%) increased prevalence of both PTB and LBW compared to those who never used antidepressants. There was no evidence that women who used antidepressants during pregnancy had a higher prevalence of the considered outcomes compared to women who used antidepressants before pregnancy, but stopped during pregnancy. Such findings were confirmed by considering separately the effects of SSRIs and other antidepressants together. Conclusions Our findings suggest that depression in itself, rather than antidepressant medication, might be implicated in the causal pathway of PTB and LBW.

Background and aims: We aimed to assess the association between exposure to statins and hospitalization for cataract. Methods: A population-based, nested case-control study was performed on a cohort of 134,441 patients from Lombardy (Italy), newly treated with statins between 2005 and 2007. Cases were patients hospitalized for cataract or lens extraction surgery after initial statin prescription until December 31, 2012. For each case patient, up to 5 controls were randomly selected from the cohort and matched by gender, age at cohort entry, and date of index prescription. Logistic regression was used to model the outcome risk associated with low (proportion of days covered, PDC 25-49%), intermediate (PDC 50-74%), and high (PDC ≥ 75%) adherence compared with very-low adherence (PDC < 25%). Results: 1334 case patients were matched to 6601 controls. Mean age (SD) of cases and controls was about 70 years (9 years) and 51% of them were men. There was a slight but continuous trend toward an increased risk of cataract as adherence to statin therapy increased in the adjusted risk models, with a significant odds ratio of 1.19 (95% CI 1.01-1.40%) for PDC 50-74% and 1.20 (95% CI 1.02-1.40) for PDC ≥ 75% vs. PDC < 25%, respectively. There was no statistical evidence that the effect of statins on cataract risk differed according to statin potency at starting therapy. Conclusions: Statin therapy was associated with a modestly increased risk of cataract surgery. Nevertheless, in view of the overwhelming benefit of statins for reduction of CV events, clinical practice for statins therapy does not need to change.

Background and aims We aimed at describing the therapeutic approach in young adult patients diagnosed with heterozygous familial hypercholesterolemia (HeFH) and their adherence and persistence to treatment. Methods From regional administrative databases, individuals aged ≤40 years, who received exemption for HeFH between January 1, 2003 and December 31, 2011, and concomitantly started statin treatment, were identified. Within the first year of treatment, we evaluated therapeutic changes, adherence as MPR (medication possession ratio), persistence as continuous drug coverage without gaps ≥60 days, and influencing factors using log binomial models. Results Of 1404 patients, 42.4% were initially treated with a high-efficacy statin. 23.4% of patients showed at least one treatment change. Mean MPR was 68.7% (29.9), and patients showing continued statin use were 47.0%. Therapy modification was significantly associated with a past cardiovascular event (relative risk, RR [95% confidential interval] 2.28 [1.69–3.09]) and at least one lipid test (RR 1.82 [1.31–2.53]). MPR ≥80% was significantly associated with the first statin prescribed (atorvastatin RR 1.28 [1.09–1.51] and rosuvastatin RR 1.21 [1.01–1.44], vs. simvastatin), a past cardiovascular event (RR 1.33 [1.12–1.59]), at least one therapy change (RR 1.28 [1.15–1.43]), at least a lipid test (RR 1.26 [1.07–1.49]). A similar pattern was observed for persistence. Conclusions This analysis of young adult HeFH patients showed that therapy change was quite frequent, and probably reflected adjustments according to individual response. Adherence and persistence were inadequate, even in this population at high cardiovascular risk, and they need to be improved through proper patient education and shared treatment decision-making approach.

Objectives Health care utilization (HCU) databases are widespread sources of data for pharmacoepidemiologic investigations. Possible confounders are typically not measured in such databases. We show how to assess the impact of confounders in a study aimed at comparing cardiovascular (CV) risk according to drug regimen prescribed at starting antihypertensive therapy, nominally one agent (monotherapy) or a combination of agents in a unique tablet (fixed-dose combination) or in at least two distinct tablets (extemporaneous combination). Study Design and Settings A nested case–control study was carried out by including the 209,650 patients from Lombardy (Italy) newly treated between 2000 and 2001. Cases were the 10,688 patients who were hospitalized for CV disease until 2007. Three controls were selected for each case. Logistic regression was used to model the CV risk associated with initial therapeutic regimen. A Monte Carlo sensitivity analysis was performed for accounting unmeasured confounders (hypertension severity and chronic disease score) by means of external adjustment with medical record (MR) data. Results Compared with patients on fixed-dose combination, those on extemporaneous combination or monotherapy, respectively, had CV risk increased to 15% (95% confidence interval [CI]: 3%, 29%) or 17% (95% CI: 8%, 26%). External adjustment did not modify the risk associated with monotherapy. In contrast, the excess of risk associated with extemporaneous combination was annulled when external adjustment was applied. Conclusion MR data can be used to assess confounding bias unmeasured from HCU database. Starting antihypertensive therapy with a combination of agents probably reduces the CV risk with respect to monotherapy, even in the setting of primary prevention.

To analyse, in older community-dwelling people living in Italy's Lombardy region, 8-year trends in new users of spironolactone co-prescribed with angiotensin-converting-enzyme inhibitors (ACE-Is) and/or angiotensin receptor blockers (ARBs); blood test monitoring; and independent predictors of appropriate blood test monitoring.The region's administrative health database from 2001 to 2008 was used to retrieve yearly frequencies of subjects aged 65+ who started this co-prescription. Multivariate analyses were adjusted for age, sex, local health unit, treatment with beta-blockers, drugs for diabetes, and polypharmacy (i.e., exposure to five or more different drugs).Only new users of spironolactone co-prescribed with ARBs increased from 2001 to 2008 (P 0.001). In the 6 months before starting the co-prescriptions 96 to 100% of patients measured serum creatinine (mean 99.3%), sodium (97.3%) and potassium (98.6%). Within 3 months of starting the co-prescriptions 96 to 99% of patients measured serum sodium (mean 97.3%) and potassium (98.6%), but on average only 48% of them (range 43 to 53%) measured serum creatinine, with an increase over time (odds ratio [change in regression per year] = 1.03, 95% CI 1.02-1.05, P 0.001). At multivariate analysis polypharmacy was found to be the only independent predictor of such creatinine monitoring (P 0.001).Our results support the need for greater awareness within the medical community of the potential renal toxicity of the association of spironolactone with ACE-Is and/or ARBs. Adequate short-term monitoring of serum creatinine in all older community-dwelling people who receive such co-prescription is necessary in order to ensure safe usage of these medications.

Background Aim of the present investigation was to quantify the early discontinuation phenomenon in patients treated for hypertension, dyslipidemia or diabetes, and to assess their clinical characteristics and incidence of cardiovascular (CV) outcomes to see whether an incorrect diagnosis was involved or treatment continuation might have been indicated. Methods Using the health-care databases on beneficiaries of the National Health Service (NHS) living in Lombardy, we studied patients aged 40-79 years who received their first prescription during 2003. Patients were classified according to whether they received only one or multiple prescriptions and data were compared with those obtained in individuals who did not receive any prescription. Crude and standardized rates of hospitalization for CV outcomes were calculated from initial prescription until 2008. Results Among the 203,302 patients on antihypertensive therapy, those experiencing only one prescription (35.7%) showed significant higher rates of cotreatments, comorbidities, and CV hospitalization than those who did not receive antihypertensive medications. Standardized CV rates were respectively 40.0 and 37.8 events every 10,000 person-year at risk (+7%). Similar findings were obtained for antidiabetic or lipid-lowering medications for which the between-group difference in CV rate was even greater (+21% and +18% respectively). Conclusions In general practice management of hypertension, dyslipidemia and diabetes is characterized by a high rate of treatment discontinuation. Patients who early discontinued had an unfavorable risk profile and a greater incidence of CV events than untreated patients. This suggests that they include candidates in whom treatment continuation is advisable.

Diabet. Med. 29, 385–392 (2012) Abstract Aims To describe trends in diagnosed diabetes prevalence, incidence and mortality from 2000 to 2007 in the most heavily populated Italian region. Methods We examined the prevalence and incidence rates of Type 1 and Type 2 diabetes and yearly mortality rates among individuals with diabetes from 2000 to 2007 using an administrative health database of prescription, disease-specific exemption and hospitalization records of more than 9 million inhabitants of Lombardy. Age- and sex-specific rates were calculated and temporal trends for subjects aged ≥ 30 years were analysed. Results The crude point diabetes prevalence rose from 3.0% in 2000 to 4.2% in 2007, a 40% increase. The incidence remained stable during the study period with a rate of 4/1000 per year. Overall mortality declined from 43.2/1000 in 2001 to 40.3/1000 in 2007 (6.7% decrease) at a rate slightly higher than that of the general population (4.8% decrease). Our projection in subjects aged ≥ 30 years indicates that the prevalence will rise continuously over the next years, reaching 11.1% in 2030. Conclusions The prevalence of diabetes increased substantially between 2000 and 2007, mainly because there are more patients with a new diagnosis each year than those who die. The increase observed by 2007 almost reached the World Health Organization prediction for 2030. Our analyses suggest that the increase will continue over the next few decades. These data are important for defining the burden of diabetes in the near future, to help in planning health services and ensure proper allocation of resources.

Aims: this study wants to estimate the economic burden of incident Acute Myocardial Infarction (AMI) registered in Lombardy (about 9.2 million residents). Method and results: a longitudinal study was conducted using a Data Warehouse (DENALI) that organised Healthcare Administrative databases of Lombardy related to eligibility criteria, hospital discharges (HDs), pharmaceutical and outpatient claims of citizens. All individuals with a HD for a first event of AMI during 2003 were identified and followed for 12 months. During 2003 12,049 individuals (64% males, mean age 70 +/-13 y.o.) had a HD for incident AMI. The total cost during the first year was € 163 million, corresponding to the 1% of the healthca re budget of Lombardy. The monthly cost in the first year was € 1,249 per person (77% attributable to HDs, 15% to pharmaceuticals and 8% to outpatient care). While most of the uptake of drugs used in secondary prevention was quick and happened in the first 3 months after the index event, the phenomenon of non persistence at 12 months was relevant. Conclusion: this large study on the burden of AMI shows the epidemiologic, economic and clinical impact of the disease. DENALI, with its large population followed over time, is a powerful and dynamic tool for epidemiologic and health economic research.

Venous thromboembolism (VTE) is an important cause of morbidity and mortality following major orthopaedic surgery. However, the incidence of VTE and the role of additional risk factors have not yet been well explored in Italian clinical practice. The objective of the study is to estimate the incidence of VTE in the 3 months following elective hip and knee replacement (HR, KR) in a large cohort of patients, and the association between some selected risk factors and the occurrence of VTE. A large cohort study based on the record linkage between automated archives of the National Health System was analysed. In particular, all the residents in the Lombardy Region (Italy) who underwent HR and KR between 2005 and 2008 were followed for 3 months after surgery. The odds ratio (OR) of VTE associated with selected known risk factors was estimated by multivariate logistic regression. Amongst the 69,770 patients included in the study, 2,393 experienced at least one VTE event during the follow-up; the overall risk of VTE after HR or KR was 3. 4%. The adjusted odds of experiencing a VTE event was higher in male patients (OR 1. 11; 95% confidence interval 1. 01-1. 21), aged 60 years or older (1. 30; 1. 00-1. 68), undergoing KR (1. 47; 1. 35-1. 61), with previous deep vein thrombosis (1. 96; 1. 20-3. 19), pulmonary embolism (3. 25; 1. 84-5. 75) or cancer (1. 21; 1. 00-1. 46). In conclusion, the incidence of VTE after elective HR and KR in the Italian clinical practice is high. Our results suggest the need of optimising the management of thromboprophylaxis to further reduce postoperative VTE. © 2011 SIMI.