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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.

Accurate staging of early non-small cell lung cancer is fundamental for selecting the best treatment. The aim of this study was to identify risk factors for nodal upstaging after video-assisted thoracoscopic lobectomy for clinical T1-3N0 tumors.From 2014 to 2017, 3276 thoracoscopic lobectomies were recorded in the prospective database "Italian VATS Group". Linear and multiple logistic regression models were adapted to identify independent predictors of nodal upstaging and factors associated with progression in postoperative N status.Nodal upstaging was found in 417 cases (12.7%), including 206 cases (6.2%) of N1-positive nodes, 81 cases of N2 nodes (2.4%), and 130 cases (4%) of involvement of both N1 + N2 nodes. A total of 241 (7.3%) patients had single-station nodal involvement, whereas 176 (5.3%) had multiple-station involvement. In the final regression model, the tumor grade, histology, pathologic T status, and 12 resected nodes were independent predictors of nodal upstaging.The number of resected lymph nodes seems to predict nodal upstaging better than the type of intraoperative lymph node management. Other preoperative risk factors correspond to those for which the current guidelines of the European Society of Thoracic Surgery recommend more extensive preoperative mediastinal staging.

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.

Objectives To describe NSAID utilization for musculoskeletal conditions in a large cohort of Italian elderly with cerebro/cardiovascular disease, a population in which NSAIDs should be generally avoided due to the prothrombotic potential. Methods Administrative data from five Italian geographic areas were analyzed. Patients aged ≥ 65 with a cerebro/cardiovascular event recorded between 2008 and 2011 (cohort entry) were selected. Prescription NSAIDs reimbursed for musculoskeletal conditions and dispensed during 1 year follow-up were retrieved to describe (i) prevalence of use, (ii) average amount of defined daily doses of NSAIDs claimed by users per day of follow-up, and (iii) distribution of the received daily dose (RDD) among patients with ≥ 2 dispensings. Among new users, i.e., patients without NSAID dispensings during 2 years before cohort entry, the first dispensed NSAID molecule was observed. Results Overall, 511,989 patients were selected. Across the five geographic areas, prevalence of use ranged from 48 to 21% and average consumption ranged between 30 and 67 DDD/1000 users/day. Around 10% of patients in the overall cohort had a RDD > 1. Nimesulide (9.6%) and diclofenac (7.5%) had the highest prevalence of use. The most consumed NSAIDs were nimesulide and coxibs with 10.6 and 7.5 DDD/1000 users/day, respectively. Among new users recruited in 2011, 30% had diclofenac or a coxibs as the first prescription. Conclusions NSAID use was common in the study cohort, particularly in central-southern areas. In contrast with current recommendations, coxibs and diclofenac were among the most prescribed active principles, even in new users. Interventions to promote appropriateness of use are warranted. Electronic supplementary material The online version of this article (10.1007/s00228-018-2411-y) contains supplementary material, which is available to authorized users.

Infections are a major complication of solid organ transplants (SOTs). This study aimed to describe recipients’ characteristics, and the frequency and etiology of infections and transplant outcome in liver and lung SOTs, and to investigate exposures associated to infection and death in liver transplant recipients. The study population included recipients of SOTs performed in Italy during a 1-year period in ten Italian lung transplant units and eight liver transplant units. Data on comorbidities, infections, retransplantation, and death were prospectively collected using a web-based system, with a 6-month follow-up. The cumulative incidence of infection was 31.7% and 47.8% in liver and lung transplants, respectively, with most infections occurring within the first month after transplantation. Gram-negatives, which were primarily multidrug-resistant, were the most frequent cause of infection. Death rates were 0.42 per 1000 recipient-days in liver transplants and 1.41 per 1000 recipient-days in lung transplants. Infection after SOT in adult liver recipients is associated to an increased risk of death (OR = 13.25; p-value < 0.001). Given the frequency of infection caused by multidrug-resistant microorganisms in SOT recipients in Italy and the heavy impact of infections on the transplant outcome, the reinforcement of surveillance and control activities to prevent the transmission of multidrug-resistant microorganisms in SOT recipients represents a priority. The implementation of the study protocol in liver and lung transplant units and the sharing of results have increased the awareness about the threat due to antimicrobial resistance in the country.

Background and Objectives: Antihypertensive treatment with calcium channel blockers (CCBs) is consolidated in clinical practice; however, different studies observed increased risks of acute events for short-acting CCBs. This study aimed to provide real-world evidence on risks of acute cardiovascular (CV) events, hospitalizations and mortality among users of different CCB classes in secondary CV prevention. Methods: Three case–control studies were nested in a cohort of Italian elderly hypertensive CV-compromised CCBs users. Cases were subjects with CV events (n = 25,204), all-cause hospitalizations (n = 19,237), or all-cause mortality (n = 17,996) during the follow-up. Up to four controls were matched for each case. Current or past exposition to CCBs at index date was defined based on molecule, formulation and daily doses of the last CCB delivery. The odds ratio (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression models. Results: Compared to past users, current CCB users had significant reductions in risks of CV events [OR 0.88 (95% CI: 0.84–0.91)], hospitalization [0.90 (0.88–0.93)] and mortality [0.48 (0.47–0.49)]. Current users of long-acting dihydropyridines (DHPs) had the lowest risk [OR 0.87 (0.84–0.90), 0.86 (0.83–0.90), 0.55 (0.54–0.56) for acute CV events, hospitalizations and mortality], whereas current users of short-acting CCBs had an increased risk of acute CV events [OR 1.77 (1.13–2.78) for short-acting DHPs; 1.19 (1.07–1.31) for short-acting non-DHPs] and hospitalizations [OR 1.84 (0.96–3.51) and 1.23 (1.08–1.42)]. Conclusions: The already-existing warning on short-acting CCBs should be potentiated, addressing clinicians towards the choice of long-acting formulations.

Purpose: Conflicting findings were observed from clinical trials and observational studies evaluating the association between the use of statins and the risk of fracture. A case–control study nested into a cohort of elderly patients on treatment with statins for cardiovascular secondary prevention was performed on this issue. Methods: The cohort was formed by 13 875 individuals aged ≥65 years from several Italian health units receiving statins after hospital discharge for cardiovascular outcomes. From this cohort, 964 patients who experienced fracture were identified (i.e., cases). Up to five controls were randomly selected for each case from the underlying cohort. Conditional logistic regression was used to model the risk of fracture associated with adherence to statins, which was measured from the proportion of days covered (PDC) by treatment. A set of sensitivity analyses was performed in order to account for sources of systematic uncertainty. Results: Compared with patients with low adherence (PDC ≤ 40%), those on intermediate (PDC 41–80%) and high (PDC > 80%) adherence exhibited a risk reduction of 21% (95% confidence interval 6% to 23%) and 25% (7% to 40%). Similar effects were observed among patients younger and older than 80 years, as well as among men, while there was no evidence that adherence to statins affected the risk of fracture among women. Sensitivity analyses revealed that the associations were consistent and robust. Conclusions: Use of statins for secondary cardiovascular prevention is associated with fracture risk reduction in elderly people. Further studies are required to better clarify the statin–fracture association in postmenopausal women. Copyright © 2017 John Wiley & Sons, Ltd.

The pathogenesis of idiopathic interstitial pneumonias (IIPs), particularly of idiopathic pulmonary fibrosis (IPF), is still unknown and the precise nature of the primum movens is strongly debated. Epithelial cells can be the first target of various environmental toxic agents. Both types of pneumocytes may be injured. Type I pneumocyte loss, however, is most conspicuous in fibroblastic foci, the principal sites where irreversible fibrogenesis starts. Epithelial regeneration is highly disturbed: cuboidal and bronchial cells are mainly involved in alveolar repair. These cells, unable to accomplish important functions of normal pneumocytes, secrete various factors inducing migration and proliferation of fibroblasts responsible for progressive extracellular matrix accumulation and lung remodelling. Endothelial cells may also be considered the major players in the initiation of fibrogenic events. Microvascular injury has been largely demonstrated as an early event in IPF lungs. Thrombin as well as other coagulation products has many biological effects such as the activation of different profibrotic factors, which in addition to other fibrogenetic molecules released by stimulated endothelium, are responsible for migration and proliferation of fibroblasts. The old pathogenesis of IPF: chronic inflammation can now be considered the principal event in other non IPF-IIPs. Among inflammatory cells, different cell types have been extensively suggested to play a key role in the pathogenesis of pulmonary fibrosis: granulocytes and eosinophils or mast cells. More recently novel mechanisms underlying the pathogenesis of pulmonary fibrosis have been proposed: bone marrow-derived stem cells may play a crucial role in the fibroproliferative response as well as in epithelial regeneration.

A 73 years-old woman presented with locally advanced breast cancer (cT4b cN1 M0, stage IIIB) and atrial flutter. Because of the arrhythmia, chemotherapy or tamoxifen, although malignancy was hormone-sensitive, were discarded. Letrozole was started. Two months later, the breast nodule and skin ulceration cleared up. Surgery was performed. Nowadays, 24 months later, patient does fine, continuing letrozole as adjuvant treatment.

With the improvement in survival rates after lung transplantation, concern has arisen about evaluating quality of life (QoL). This multicenter cross-sectional study aimed at describing QoL and identifying factors associated with it.We assessed QoL in 129 lung transplant recipients from 5 centres in Italy, during scheduled follow-up visits, using the SF-36, GHQ and St George's respiratory questionnaires (SGRQ).The SF-36 elicited impaired QoL in the physical, but not in the mental domains (PCS = 44; MCS = 53). The GHQ identified 29 patients (23%) with psychological discomfort and the SGRQ scores were significantly better than those of patients with chronic respiratory disease. On multivariate analysis, exertional dyspnea was an independent predictor of the PCS (adjusted delta -6.3 (p0.001), while osteoporosis (delta = -3.1), BOS (delta = -4.3), acute rejection (delta = -3.9) and heart and lung transplant (delta = +6.4) were only marginally associated. Dyspnea was also related to a GHQ score5.The study identified exertional dyspnea as the main determinant of QoL as measured both by SF36 (PCS) and GHQ. Other objective measures contributed only to the PCS. Thus, the SF-36 (PCS) and GHQ were useful in identifying patients who needed treatment not only for complications but also psychological support and continued physical rehabilitation.

Background The novel coronavirus (SARS-CoV-2) pandemic spread rapidly worldwide increasing exponentially in Italy. To date, there is lack of studies describing clinical characteristics of the people at high risk of infection. Hence, we aimed (i) to identify clinical predictors of SARS-CoV-2 infection risk, (ii) to develop and validate a score predicting SARS-CoV-2 infection risk, and (iii) to compare it with unspecific scores. Methods Retrospective case-control study using administrative health-related database was carried out in Southern Italy (Campania region) among beneficiaries of Regional Health Service aged over than 30 years. For each person with SARS-CoV-2 confirmed infection (case), up to five controls were randomly matched for gender, age and municipality of residence. Odds ratios and 90% confidence intervals for associations between candidate predictors and risk of infection were estimated by means of conditional logistic regression. SARS-CoV-2 Infection Score (SIS) was developed by generating a total aggregate score obtained from assignment of a weight at each selected covariate using coefficients estimated from the model. Finally, the score was categorized by assigning increasing values from 1 to 4. Discriminant power was used to compare SIS performance with that of other comorbidity scores. Results Subjects suffering from diabetes, anaemias, Parkinson’s disease, mental disorders, cardiovascular and inflammatory bowel and kidney diseases showed increased risk of SARS-CoV-2 infection. Similar estimates were recorded for men and women and younger and older than 65 years. Fifteen conditions significantly contributed to the SIS. As SIS value increases, risk progressively increases, being odds of SARS-CoV-2 infection among people with the highest SIS value (SIS = 4) 1.74 times higher than those unaffected by any SIS contributing conditions (SIS = 1). Conclusion Conditions and diseases making people more vulnerable to SARS-CoV-2 infection were identified by the current study. Our results support decision-makers in identifying high-risk people and adopting of preventive measures to minimize the spread of further epidemic waves.

Objectives A prospective cohort study was conducted in Italy in order to describe the microbiologic aspects of colonization/infection by carbapenemase-producing Enterobacteriaceae (CPE) in donors and recipients of lung and liver transplants and the possible CPE transmission from donors to recipients. Methods Between 15 January 2014 and 14 January 2015, all recipients of solid organ transplants (SOT) at ten lung and eight liver transplantation centres and the corresponding donors were enrolled. Screening cultures to detect CPE were performed in donors, and screening and clinical cultures in recipients with a 28-day microbiologic follow-up after receipt of SOT. Detection of carbapenemase genes by PCR, genotyping by multilocus sequence typing, and pulsed-field gel electrophoresis and whole-genome sequencing were performed. Results Of 588 screened donors, 3.4% were colonized with CPE. Of the liver first transplant recipients (n = 521), 2.5% were colonized before receipt of SOT and 5% acquired CPE during follow-up. CPE colonization was higher in lung first transplant recipients (n = 111, 2.7% before SOT and 14.4% after SOT). CPE infections occurred in 1.9% and 5.3% of liver or lung recipients, respectively. CPE isolates were mostly Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae belonging to CG258. Three events of donor–recipient CPE transmission, confirmed by whole-genome sequencing and/or pulsed-field gel electrophoresis, occurred in lung recipients: two involving K. pneumoniae sequence type 512 and one Verona integron-encoded metallo-β-lactamase (VIM)-producing Enterobacter aerogenes. Conclusions This study showed a low risk of donor–recipient CPE transmission, indicating that donor CPE colonization does not necessarily represent a contraindication for donation unless colonization regards the organ to be transplanted. Donor and recipient screening remains essential to prevent CPE transmission and cross-infection in transplantation centres.

ObjectiveTo develop and validate a novel comorbidity score (multisource comorbidity score (MCS)) predictive of mortality, hospital admissions and healthcare costs using multiple source information from the administrative Italian National Health System (NHS) databases.MethodsAn index of 34 variables (measured from inpatient diagnoses and outpatient drug prescriptions within 2 years before baseline) independently predicting 1-year mortality in a sample of 500 000 individuals aged 50 years or older randomly selected from the NHS beneficiaries of the Italian region of Lombardy (training set) was developed. The corresponding weights were assigned from the regression coefficients of a Weibull survival model. MCS performance was evaluated by using an internal (ie, another sample of 500 000 NHS beneficiaries from Lombardy) and three external (each consisting of 500 000 NHS beneficiaries from Emilia-Romagna, Lazio and Sicily) validation sets. Discriminant power and net reclassification improvement were used to compare MCS performance with that of other comorbidity scores. MCS ability to predict secondary health outcomes (ie, hospital admissions and costs) was also investigated.ResultsPrimary and secondary outcomes progressively increased with increasing MCS value. MCS improved the net 1-year mortality reclassification from 27% (with respect to the Chronic Disease Score) to 69% (with respect to the Elixhauser Index). MCS discrimination performance was similar in the four regions of Italy we tested, the area under the receiver operating characteristic curves (95% CI) being 0.78 (0.77 to 0.79) in Lombardy, 0.78 (0.77 to 0.79) in Emilia-Romagna, 0.77 (0.76 to 0.78) in Lazio and 0.78 (0.77 to 0.79) in Sicily.ConclusionMCS seems better than conventional scores for predicting health outcomes, at least in the general population from Italy. This may offer an improved tool for risk adjustment, policy planning and identifying patients in need of a focused treatment approach in the everyday medical practice.

Background Aim of our study was to compare adherence to antihypertensive drug therapy between newly treated patients in whom monotherapy or a 2-drug single-pill combination (SPC) was initially dispensed. Methods The 63,448 residents of Lombardy Region (Italy), aged 40–80 years, who were newly treated with antihypertensive drugs during 2016, were identified and followed for 1 year after the first prescription. The outcome of interest was adherence to drug therapy that was measured according to the “proportion of days covered” (PDC) criterion, i.e., the ratio between the number of days in which the drug was available and the days of follow-up. Patients who had a PDC >75% and Results About 46% and 17% of patients showed high and poor adherence, respectively. Compared with patients under initial monotherapy (85%), those who were initially treated with a SPC (15%) had higher propensity to be highly adherent and a lower propensity to be poorly adherent to antihypertensive treatment (risk ratio: 1.18, 95% confidence interval 1.16–1.21; 0.42, 0.39–0.45, respectively). This was the case regardless the sex, the age, the patient clinical status, and with almost any type of SPC. Conclusions In a real-life setting, patients who were initially prescribed a 2-drug SPC exhibited more frequently a good adherence to antihypertensive treatment than those starting with a single drug.

Objective: to investigate both muscular manifestations and CK levels of a large cohort of patients with COVID-19 infection and to determine whether hyperckemia is associated with morbidity and mortality.Methods: Data of 615 patients discharged from ASST Ovest Milanese (Milan, Lombardy, Italy) with final diagnosis of COVID-19 infection were retrospectively extracted from electronical medical records from 21 February to 1 May 2020. Patients were descriptively analyzed with respect to the following variables: sex, age, muscular manifestations (including myalgia/arthralgia and fatigue), respiratory involvement (SARS pneumonia or respiratory failure) and history of falls. Association between patients’ characteristics and CK levels was investigated. In addition, the proportion of patients who died following access to the ER was calculated. Finally, the effect of CK levels and other patients’ features on mortality was estimated using a logistic regression model.Results: 176 (28.6%) patients had raised serum CK levels. 88 (14.3%) had muscular manifestations, of which 81 (13.2%) complained fatigue and 17 (2.8%) had myalgia and/or arthralgia. CK levels were significantly associated with respiratory involvement and fatal outcome.Conclusions: Our study provides preliminary evidence that hyperckemia is a predictor of respiratory involvement and fatal outcome in patients with COVID-19 infection. For patients with muscle damage symptoms, screening for COVID-19 infection is recommended together with the dosage of CK level.

Purpose. Randomised controlled trials have shown that renal denervation lowers office and ambulatory blood pressure. The aim of the present study was to evaluate whether patients undergoing renal denervation procedure in a real-life setting have a reduction in antihypertensive drug prescription over the subsequent years. Material and methods. Using the healthcare utilisation database of the Lombardy Region (Italy), the 136 patients who, during the period 2011–2016, were prescribed four or more antihypertensive drugs and underwent renal denervation were included in the study cohort. The number and type of antihypertensive drugs were assessed over the year before and during the three-year period after renal denervation. Results. The median age of the patients was 67 years and 68% of them were men. Based on a multisource comorbidity score, about 40% of patients showed a poor or very poor clinical status. Before renal denervation, the majority of the patients were prescribed four or five antihypertensive drugs. The number of drugs decreased after the denervation and reached 55% after three years. Over the same period, patients prescribed six drugs decreased from 18% to 2%. All antihypertensive drugs were less prescribed throughout the post denervation period. Compared to the year before the denervation, after three years prescription of diuretics was reduced by 15%, calcium channel blockers by 21%, ACE-inhibitors by 32%, angiotensin receptor blockers by 22%, beta-blockers by 20%, and alfa-blockers by 30%. Use of antihypertensive drugs exhibited a reduction also in an age, sex, and clinically matched control group with no renal denervation to an extent, however, much lower than in denervated patients (p-value = 0.013). Conclusion. In the real-life setting, patients who underwent renal denervation had a clearcut reduction in antihypertensive drug prescription over the following years.Plain Language SummaryPatients exhibited a reduction in the prescription of antihypertensive drugs during the three years that followed the denervation procedureThe decrease in the number of antihypertensive drugs was marked, started after a relatively short time (six months), and involved all drugs prescribed before the denervationThe number of hospitalisations for a cardiovascular event was similar before and after renal denervationAlbeit blood pressure values were not recorded in our database, all these findings taken together suggest the renal denervation procedure has a favourable influence on blood pressure control and is not associated with an increase in the risk of major cardiovascular complications Patients exhibited a reduction in the prescription of antihypertensive drugs during the three years that followed the denervation procedure The decrease in the number of antihypertensive drugs was marked, started after a relatively short time (six months), and involved all drugs prescribed before the denervation The number of hospitalisations for a cardiovascular event was similar before and after renal denervation Albeit blood pressure values were not recorded in our database, all these findings taken together suggest the renal denervation procedure has a favourable influence on blood pressure control and is not associated with an increase in the risk of major cardiovascular complications

OBJECTIVES: The aim of the study was to assess clinical presentation, endoscopic findings, antibiotic susceptibility and treatment success of Helicobacter pylori (H. pylori) infected pediatric patients. METHODS: Between 2013 and 2016, 23 pediatric hospitals from 17 countries prospectively submitted data on consecutive H. pylori-infected (culture positive) patients to the EuroPedHP-Registry. RESULTS: Of 1333 patients recruited (55.1% girls, median age 12.6 years), 1168 (87.6%) were therapy naïve (group A) and 165 (12.4%) had failed treatment (group B). Patients resided in North/Western (29.6%), Southern (34.1%) and Eastern Europe (23.0%), or Israel/Turkey (13.4%). Main indications for endoscopy were abdominal pain or dyspepsia (81.2%, 1078/1328). Antral nodularity was reported in 77.8% (1031/1326) of patients, gastric or duodenal ulcers and erosions in 5.1% and 12.8%, respectively. Primary resistance to clarithromycin (CLA) and metronidazole (MET) occurred in 25% and 21%, respectively, and increased after failed therapy. Bacterial strains were fully susceptible in 60.5% of group A, but in only 27.4% of group B. Primary CLA resistance was higher in Southern and Eastern Europe (adjusted odds ratio [ORadj] = 3.44, 95% confidence interval [CI] 2.22-5.32, P, SCOPUS: ar.j, info:eu-repo/semantics/published

Background Pregnant women who suffer from depressive disorders are likely to be treated with antidepressant (AD) medications. Recent meta-analyses underlined the possible relation between AD use and several neonatal outcomes, although the underlying mechanisms remains unclear. Methods To summarise and evaluate the associations between AD use in pregnancy and neonatal outcomes, we conducted an umbrella review of meta-analyses of observational studies published up to December 2019 in PubMed and Embase. Summary risk estimates for the associations between use of AD as a whole, or specific AD classes and drugs, and the risk of neonatal outcomes were reported. Results Our review included 22 meta-analyses investigating 69 associations. However, none were supported by convincing evidence. Highly suggestive evidence regarded the associations between (i) any time AD exposure and the risk of preterm birth (relative risk, 1.68; 95% confidence interval 1.52, 1.86), (ii) any time exposure to selective serotonin reuptake inhibitors (SSRIs) and the risk of preterm birth (1.43; 1.22, 1.37) and (iii) respiratory distress (1.33; 1.14, 1.55), and (iv) SSRI exposure during the first trimester of pregnancy and the risk of cardiovascular malformations (1.25; 1.13, 1.39). Suggestive evidence was obtained for any time AD exposure on 1-min low Apgar score (absolute average difference, −0.34; −0.53, −0.14). Conclusions Overall, the effects of AD exposure during pregnancy on neonatal outcomes have been extensively studied, but few of the associations are graded as high quality evidence. More prospective studies and large collaborations with comprehensive standardised reporting of analyses are needed.

Purpose The purpose of this study was to assess the possible relation between use of antidepressant (AD) drugs, that is, tricyclic ADs, selective serotonin reuptake inhibitors (SSRIs), and atypical ADs (AAs), and the risk of hospitalization for cardiovascular (CV) events among older patients with previous CV diseases. Methods A nested case-control study was carried out among patients aged 65 years and older from 5 Italian health care territorial units who were discharged for CV disease during 2008 to 2010. The cohort was composed by 344,747 individuals, and of these, 97,739 (28%) experienced hospital admission for CV events (myocardial infarction, arrhythmia, stroke, heart failure) during follow-up (until 2014) and were included as cases. Up to 5 controls were randomly selected and matched to each. A conditional logistic regression was fitted to estimate the risk of CV events associated with ADs past or current use. A within-patient comparison was performed by the case-crossover design to account the effect of depression. Findings Current users of SSRIs and AAs were at increased risk of CV events with odds ratios of 1.25 (95% confidence interval, 1.21-1.29) and 1.31 (1.25-1.37), respectively. An increased risk of arrhythmia and stroke was associated with current use of SSRIs and AAs, whereas an increased risk of heart failure was detected with current use of any ADs. The results were confirmed by the case-crossover approach. Implications Evidence that AD use is associated with an increased risk of CV events in accordance with specific mechanisms of action among older people with CV disease was added by this study.

OBJECTIVES Although it has been postulated that patients might benefit from the centralization of high-volume specialized centres, conflicting results have been reported on the relationship between the number of lung resections performed and the long-term, all-cause mortality rates among patients who underwent surgery for lung cancer. A population-based observational study was performed to contribute to the ongoing debate. METHODS The 2613 patients, all residents of the Lombardy region (Italy), who underwent lung resection for lung cancer from 2012 to 2014 were entered into the cohort and were followed until 2018. The hospitals were classified according to the annual number of pulmonary resections performed. Three categories of lung resection cases were identified: low (≤30), intermediate (31–95) and high (>95). The outcome of interest was all-cause death. A frailty model was used to estimate the death risk associated with the categories of numbers of lung resections performed, taking into account the multilevel structure of the data. A set of sensitivity analyses was performed to account for sources of systematic uncertainty. RESULTS The 1-year and 5-year survival rates of cohort members were 90% and 63%. Patients operated on in high-volume centres were on average younger and more often women. Compared to patients operated on in a low-volume centre, the mortality risk exhibited a significant, progressive reduction as the numbers of lung resections performed increased to intermediate (−13%; 95% confidence interval +10% to −31%) and high (−26%; 0% to −45%). Sensitivity analyses revealed that the association was consistent. CONCLUSIONS Further evidence that the volume of lung resection cases performed strongly affects the long-term survival of lung cancer patients has been supplied.

Objective Several factors affect adherence to antihypertensive drug treatment, but whether these factors include a sex difference is unclear. Aim of the study was to compare persistence with antihypertensive drug therapy between men and women in a large cohort of patients. Methods The 60 526 residents of the Italian Lombardy Region aged 40-80 years newly treated with antihypertensive drugs during 2010 were identified and followed for 1 year after the first prescription. Discontinuation of treatment was defined as lack of prescription renewal for at least 90 days. Log-binomial regression models were fitted to estimate the risk ratio of treatment discontinuation in relation to sex. Other than for the whole population, analyses were stratified according to age, comorbidity status and the initial antihypertensive treatment strategy. Results Thirty-seven percent of the patients discontinued the drug treatment during follow-up. Compared with women, men had a 10% lower risk of discontinuation of drug treatment (95% confidence interval: 8-12). Persistence on antihypertensive treatment was better in men than in women, this being the case in both younger (40-64 years) and older patients (65-80 years), in patients starting treatment with any major antihypertensive drug and in patients who had a low comorbidity status. There was no evidence that men and women had a different risk of treatment discontinuation when their comorbidity status was worse, or initial antihypertensive treatment was based on drug combinations. Conclusion Our data show that in a real-life setting, men are more persistent to antihypertensive drug therapy than women.

Objectives The aim of this study was to develop a new population-based risk stratification tool (Chronic Related Score [CReSc]) for predicting 5-year mortality and other outcomes. Study Design and Setting The score included 31 conditions selected from a list of 65 candidates whose weights were assigned according to the Cox model coefficients. The model was built from a sample of 5.4 million National Health Service (NHS) beneficiaries from the Italian Lombardy Region and applied to the remaining 2.7 million NHS beneficiaries. Predictive performance was assessed by discrimination and calibration. CReSc ability in predicting secondary endpoints (i.e., hospital admissions and health care costs) was investigated. Finally, the relationship between CReSc and income was considered. Results Among individuals aged 50–85 years, CReSc performance showed (1) an area under the receiver operating characteristic curve of 0.730, (2) an improved reclassification from 44% to 52% with respect to other scores, and (3) a remarkable calibration. A trend toward increasing rates of all the considered endpoints as CReSc increases was observed. Compared with individuals on low–intermediate income, NHS beneficiaries on high income showed better CReSc profile. Conclusion We developed a risk stratification tool able to predict mortality, costs, and hospital admissions. The application of CReSc may generate clinically and operationally important effects.

Background: Limited evidence is available on the safety and efficacy of antimicrobials during pregnancy, with even less according to the trimester of their use. Objective: This study aimed to evaluate the association between exposure to antibiotics therapy (AT) during pregnancy and short-term neonatal outcomes. Methods: We considered 773,237 deliveries that occurred between 2007–2017 in the Lombardy region of Italy. We evaluated the risk of neonatal outcomes among infants that were born to mothers who underwent AT during pregnancy. The odds ratios and the hazard ratios, with the 95% confidence intervals, were estimated respectively for early (first/second trimester) and late (third trimester) exposure. The propensity score was used to account for potential confounders. We also performed subgroup analysis for the class of AT. Results: We identified 132,024 and 76,921 singletons that were exposed to AT during early and late pregnancy, respectively. Infants born to mothers with early exposure had 17, 11, and 16% increased risk of preterm birth, low birth weight, and low Apgar score, respectively. Infants that were exposed in late pregnancy had 25, 11, and 13% increased risk of preterm birth, low birth weight, and low Apgar score, respectively. The results were consistent in the subgroup analysis. Conclusion: Our results suggested an increased risk of several neonatal outcomes in women exposed to ATs during pregnancy, albeit we were not able to assess to what extent the observed effects were due to the infection itself. To reduce the risk of neonatal outcomes, women that are prescribed AT during pregnancy should be closely monitored.

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.

Background and aims To validate a set of indicators for monitoring the quality of care of patients with diabetes in ‘real-life’ practice through its relationship with measurable clinical outcomes and healthcare costs. Methods and results A population-based cohort study was carried out by including the 20,635 patients, residents in the Lombardy Region (Italy), who in the year 2012 were newly taken-in-care for diabetes. Adherence with clinical recommendations (i.e., controls for glycated haemoglobin, lipid profile, urine albumin excretion and serum creatinine) was recorded during the first year after the patient was taken-in-care, and categorized according whether he/she complied with none or almost none (0 or 1), just some (2) or all or almost all (3 or 4) the recommendations, respectively denoted as poor, intermediate and high adherence. Short- and long-term complications of diabetes, and healthcare cost incurred by the National Health Service, were assessed during follow-up. Compared with patients with poor adherence, those with intermediate and high adherence respectively showed (i) a delay in outcome occurrence of 13 days (95% CI, -2 to 27) and 23 days (9 to 38), and (ii) a lower healthcare cost of 54 € and 77 €. In average, a gain of 18 Euros and 15 Euros for each day free from diabetic complication by increasing adherence respectively from poor to intermediate and from poor to high were observed. Conclusion Close control of patients with diabetes through regular clinical examinations must be considered the cornerstone of national guidance, national audits, and quality improvement incentive schemes.

This study aimed to illustrate and account for immortal time bias in pregnancy observational investigations, using the relationship between late use of antibiotics and risk of preterm birth as an example. We conducted a population-based cohort study including 549,082 deliveries between 2007 and 2017 in Lombardy, Italy. We evaluated the risk of preterm births, low birth weight, small for gestational age, and low Apgar score associated with antibiotic dispensing during the third trimester of pregnancy. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of the outcomes, considering the use of antibiotics as time-fixed (with biased classification of exposure person-time) and time-varying (with proper classification of exposure person-time) exposure. There were 23,638 (4.3%) premature deliveries. There was no association between time-fixed exposure to antibiotics and preterm delivery (adjusted HR 0.96, 95% CI 0.92 to 1.01) but an increased risk of preterm birth when time-varying exposure to antibiotics was considered (1.27, 1.21 to 1.34). The same trend was found for low birth weight and low Apgar score. Immortal time bias is a common and sneaky trap in observational studies involving exposure in late pregnancy. This bias could be easily avoided with suitable design and analysis.

Aim of our study was to assess the relationship between adherence with antihypertensive drugs and the risk of death in frail versus nonfrail old individuals. Using the database of the Lombardy Region (Italy), we identified 1 283 602 residents aged ≥65 years (mean age 76) who had ≥3 prescriptions of antihypertensive drugs between 2011 and 2012. A nested case-control design was applied, with cases being the cohort members who died during the observation period (7 years). Logistic regression was used to model the association of interest, with adjustment for potential confounders. Adherence was measured by the proportion of the follow-up covered by prescriptions, and the analysis was separately performed in patients with a good, medium, poor, and very poor clinical status, as assessed by a score that has been shown to be a sensitive predictor of death in the Italian population. The 7-year death probability increased from 16% (good) to 64% (very poor) clinical status. Compared with patients with very low adherence with antihypertensive treatment (75% of time covered by prescriptions) exhibited a lower risk of all-cause mortality in each group, the difference decreasing progressively (−44%, −43%, −40%, and −33%) from the good to the very poor clinical status. Adherence with antihypertensive drug treatment was also associated with a lower risk of cardiovascular mortality. Adherence with antihypertensive appears to be protective in frail old patients, but the benefit is less marked than in patients with a good clinical status.

Objectives Because observational studies often use imperfect measurements, results are prone to misclassification errors. We used as a motivating example the possible teratogenic risks of antiemetic agents in pregnancy since a large observational study recently showed that first-trimester exposure to doxylamine-pyridoxine was associated with significantly increased risk of congenital malformations as a whole, as well as central nervous system defects, and previous observational studies did not show such associations. A meta-analysis on this issue was carried out with the aim to illustrate how differential exposure and outcome misclassifications may lead to uncertain conclusions. Methods Medline, searched to October 2019 for full text papers in English. Summary Odds Ratios (ORs) with confidence intervals (CIs) were calculated using random-effect models. Probabilistic sensitivity analyses were performed for evaluating the extension of differential misclassification required to account for the exposure-outcome association. Results Summary ORs were 1.02 (95 % CI, 0.92–1.15), 0.99 (0.82–1.19) and 1.25 (1.08–1.44) for overall congenital, cardiocirculatory, and central nervous system malformations respectively. By assuming exposure and outcome bias factor respectively of 0.95 (i.e., newborns with congenital defects had exposure specificity 5% lower than healthy newborns) and 1.12 (i.e., exposed newborns had outcome sensitivity 12 % higher than unexposed newborns), summary OR of central nervous system defects became 1.13 (95 % CI, 0.99–1.29) and 1.17 (95 % CI, 0.99–1.38). Conclusion Observational investigations and meta-analyses of observational studies need cautious interpretations. Their susceptibility to several, often sneaky, sources of bias should be carefully evaluated.

Aim To provide information on the balance between the cardiovascular (CV) benefit and the diabetogenic harm of statin therapy in the current clinical practice. Methods All the 115,939 residents (older than 50 years) in the Italian Lombardy Region newly treated with statins between 2003 and 2005, were followed from the first statin prescription until 2012 to identify those experiencing a macrovascular complication and those with at least one sign suggestive of new onset diabetes. The proportion of days of follow-up covered by statin prescriptions measured adherence with statins. Hazard ratio, and relative 95% confidence interval (CI), for the two considered outcomes associated with statin adherence, were separately estimated (proportional hazard models). Number needed to treat (NNT) and number needed to harm (NNH), i.e., number of individuals who must be treated with statins in order to prevent a macrovascular complication, or to generate a new onset diabetes, respectively, were calculated to evaluate the balance between CV benefit and diabetogenic harm of statin therapy. Results Compared to those at very low adherence with statins, patients at high adherence showed a significant reduction of macrovascular risk (28%, 95% CI: 23%–33%) and a greater risk of developing diabetic condition (67%, 50%-86%). In the whole cohort, the NNT was 26, whereas the NNH 65. NNT was lower than NNH also in all considered strata of age, gender, clinical profile. Conclusions This large cohort investigation provides real-world evidence that the balance between CV benefit and diabetogenic harm of statin therapy is largely favourable to treatment benefits.

Background Multimorbidity is a growing concern for healthcare systems, with many countries experiencing demographic transition to older population profiles. A simple multisource comorbidity score (MCS) has been recently developed and validated. A very large real-world investigation was conducted with the aim of measuring inequalities in the MCS distribution across Italy. Methods Beneficiaries of the Italian National Health Service aged 50–85 years who in 2018 were resident in one of the 10 participant regions formed the study population (15.7 million of the 24.9 million overall resident in Italy). MCS was assigned to each beneficiary by categorizing the individual sum of the comorbid values (i.e. the weights corresponding to the comorbid conditions of which the individual suffered) into one of the six categories denoting a progressive worsening comorbidity status. MCS distributions in women and men across geographic partitions were compared. Results Compared with beneficiaries from northern Italy, those from centre and south showed worse comorbidity profile for both women and men. MCS median age (i.e. the age above which half of the beneficiaries suffered at least one comorbidity) ranged from 60 (centre and south) to 68 years (north) in women and from 63 (centre and south) to 68 years (north) in men. The percentage of comorbid population was lower than 50% for northern population, whereas it was around 60% for central and southern ones. Conclusion MCS allowed of capturing geographic variability of multimorbidity prevalence, thus showing up its value for addressing health policy in order to guide national health planning.

ObjectivesPoor worldwide rate of blood pressure control is largely due to poor adherence to antihypertensive (AHT) drug treatment. The question of whether sex affects adherence has long been debated but conflicting findings have been reported on this issue. Our objective was to evaluate sex differences in the adherence to AHT therapy.Research design and methodsStudies were identified through a systematic search of PubMed, CINAHL, PsycINFO, Web of Science and Google Scholar (through January 2020) and manual handsearching of relevant articles. Observational studies reporting adherence to AHT drugs measured by self-report or pharmacy refill prescription-based methods among men and women were included. Summarised estimates of ORs with 95% CIs were calculated using random-effects model and meta-regression models.ResultsFrom 12 849 potentially relevant publications, 82 studies (15 517 457 men and 18 537 599 women) were included. No significant between-sex differences in adherence to AHT were observed, whether all study-specific estimates were summarised (ORs 1.04, 95% CI 1.00 to 1.09, p=0.07), nor estimates were pooled according to the method for measuring adherence. Among patients aged 65 years or older, lower self-reported adherence was observed in women (ORs 0.84, 95% CI 0.72 to 0.97, p=0.02), while the main result remained unchanged according to other subgroup analyses.ConclusionsDefinitive evidence of sex differences in adherence to AHT therapy cannot be drawn. Our little knowledge about factors affecting adherence, in particular of sex effect among elderly, urgently requires high-quality studies investigating these issues.

Background A set of indicators to assess the quality of care for women operated for breast cancer was developed by an expert working group of the Italian Health Ministry in order to compare the Italian regions. A study to validate these indicators through their relationship with survival was carried out. Methods The 16,753 women who were residents in three Italian regions (Lombardy, Emilia-Romagna and Lazio) and hospitalized for breast cancer surgery during 2011 entered the cohort and were followed until 2016. Adherence to selected recommendations (i.e., surgery timeliness, medical therapy timeliness, appropriateness of complementary radiotherapy and mammographic follow-up) was assessed. Multivariable proportional hazards models were fitted to estimate hazard ratios for the association between adherence with recommendations and the risk of all-cause mortality. Results Adherence to recommendations was 53% for medical therapy timeliness, 73% for appropriateness of mammographic follow-up, 74% for surgery timeliness and 82% for appropriateness of complementary radiotherapy. Risk reductions of 26%, 62% and 56% were observed for adherence to recommendations on medical therapy timeliness, appropriateness of complementary radiotherapy and mammographic follow-up, respectively. There was no evidence that mortality was affected by surgery timeliness. Conclusions Clinical benefits are expected from improvements in adherence to the considered recommendations. Close control of women operated for breast cancer through medical care timeliness and appropriateness of radiotherapy and mammographic monitoring must be considered the cornerstone of national guidance, national audits, and quality improvement incentive schemes., Highlights • 4 indicators to assess the quality of care in operated breast cancer were developed. • High heterogeneity across regions in breast cancer-related care was observed. • Almost all the indicators are associated with improved overall survival. • Benefits are expected from improving adherence with the considered recommendations.

Introduction Acute otitis media (AOM) is the most common childhood disease leading to antibiotic use. More than 80% of children under three years of age experience at least one episode, and about one-third of these report significant recurrence of episodes. In recent years, several studies reported that normal nasopharyngeal flora inhibits growth of common otopathogens, suggesting that maintenance of an “adequate” nasopharyngeal flora might prevent occurrence of upper respiratory tract infections, including AOM. This study aims to determine whether five-month treatment with Streptococcus salivarius 24SMB and Streptococcus oralis 89a nasal spray prevents recurrence of AOM and prescription of antibiotics in children with diagnosis of recurrent AOM. Methods Observational prospective cohort study including children aged 1–6 years with diagnosis of recurrent AOM registered with 31 Italian family pediatricians. 81 children were enrolled in the study from September 2016 to the end of the five therapeutic cycles of the Streptococcus salivarius 24SMB and Streptococcus oralis 89a supplied 7 days each month for 5 consecutive months. For each treated child, one untreated control was randomly selected, 1:1 matched for gender, age, and follow-up. Results 158 children (79 treated and 70 untreated) were included into the analysis (mean age, 3.9 years; 47% female). Univariate analysis showed a statistically significant 34% (95% CI 1%–56%) reduction in number of AOM episodes in treated children compared with those not treated. Significantly fewer antibiotics were dispensed among treated children (24%, 95% CI 1%–41%). Conclusions Our findings suggest that intermittent treatment of children with diagnosis of recurrent AOM with nasal spray containing Streptococcus salivarius 24SMB and Streptococcus oralis 89a for a period of five months might be effective in preventing antibiotic use associated with recurrent episodes of AOM. Additional larger studies to address this important clinical problem are recommended.

Aims: Guidelines support use of drug combinations in most hypertensive patients, and recently treatment initiation with two drugs has been also recommended. However, limited evidence is available on whether this leads to greater cardiovascular (CV) protection compared to initial monotherapy. Methods and results: Using the healthcare utilization database of the Lombardy Region (Italy), the 44 534 residents of the region (age 40-80 years) who in 2010 started treatment with one antihypertensive drug (n = 37 078) or a two-drug fixed-dose combination (FDC, n = 7456) were followed for 1 year after treatment initiation to compare the risk of hospitalization for CV disease associated with the two treatment strategies. To limit the confounding associated with non-randomized between-group comparisons, data were also analysed by: (i) matching the two groups by the high-dimensional propensity score (HDPS) and (ii) comparing, in patients experiencing one or more CV events (n = 2212), the CV event incidence during subperiods in which patients were prescribed mono- or FDC therapy (self-controlled case series design). Compared to initial monotherapy, patients on initial FDC therapy showed a reduced 1 year risk of hospitalization for any CV event (-21%, P

Introduction: Nimesulide is the most prescribed non-steroidal anti-inflammatory drug in Italy, and it is currently marketed in about 50 countries worldwide. The association between the use of nimesulide in early pregnancy and the risk of birth defects was investigated in a large cohort of pregnant women from Italy. Methods: Data were from the healthcare utilization databases of the Italian region of Lombardy. The cohort of 353,081 newborns occurring in Lombardy during the period 2005–2010 was investigated. Exposure to nimesulide during the first trimester of pregnancy, and congenital malformations detected at presentation and within 90 days after birth (outcome), were investigated. Exposure–outcome association was measured by the ratio between the prevalence of congenital malformations among users and non-users of nimesulide. Propensity score stratification was used to control for potential confounders, including maternal medical comorbidities, concomitant medications and sociodemographic characteristics. Results: The 627 (0.18%) women who filled prescriptions for nimesulide in the first trimester of pregnancy had a 2.6-fold risk of having children with congenital urinary tract anomalies compared to those who did not (adjusted prevalence ratio 2.6; 95% CI 1.2–5.7). Weaker and non-significant evidence for congenital malformations as a whole was found (adjusted prevalence ratio 1.2, 95% CI 0.9–1.6). Conclusion: Our study suggests that the use of nimesulide in early pregnancy may result in a greater risk of having births with congenital urinary tract anomalies. Funding: This study was funded by grants from the Italian Ministry of the Education, University and Research (’Fondo d’Ateneo per la Ricerca’ portion, year 2015)

Key Points Question What are the clinical implications of statin discontinuation in older patients receiving polypharmacy? Findings In this population-based cohort study of 29 047 patients, there was evidence that discontinuing therapy with statins was associated with a significantly increased risk of hospital admission for heart failure and any cardiovascular outcome, death from any cause, and emergency admission for any cause. Meaning The findings of this study suggest that discontinuing statins while maintaining other drug therapies may increase the long-term risk of fatal and nonfatal cardiovascular outcomes., This population-based cohort study assesses the clinical implications of discontinuing the use of statins while maintaining other drugs in a cohort of older patients receiving polypharmacy., Importance Polypharmacy is a major health concern among older adults. While deprescribing may reduce inappropriate medicine use, its effect on clinical end points remains uncertain. Objective To assess the clinical implications of discontinuing the use of statins while maintaining other drugs in a cohort of older patients receiving polypharmacy. Design, Setting, and Participants This retrospective, population-based cohort study included the 29 047 residents in the Italian Lombardy region aged 65 years or older who were receiving uninterrupted treatment with statins, blood pressure–lowering, antidiabetic, and antiplatelet agents from October 1, 2013, until January 31, 2015, with follow-up through June 30, 2018. Data were collected using the health care utilization database of Lombardy region in Italy. Data analysis was conducted from March to November 2020. Exposures Cohort members were followed up to identify those who discontinued statins. Among this group, those who maintained other therapies during the first 6 months after statin discontinuation were 1:1 propensity score matched with patients who discontinued neither statins nor other drugs. Main Outcome and Measures The pairs of patients discontinuing and maintaining statins were followed up from the initial discontinuation until June 30, 2018, to estimate the hazard ratios (HRs) and 95% CIs for fatal and nonfatal outcomes associated with statin discontinuation. Results The full cohort inclued 29 047 patients exposed to polypharmacy (mean [SD] age, 76.5 [6.5] years; 18 257 [62.9%] men). Of them, 5819 (20.0%) discontinued statins while maintaining other medications, and 4010 (68.9%) of them were matched with a comparator. In the discontinuing group, the mean (SD) age was 76.5 (6.4) years, 2405 (60.0%) were men, and 506 (12.6%) had Multisource Comorbidity Scores of 4 or 5. In the maintaining group, the mean (SD) age was 76.1 (6.3) years, 2474 (61.7%) were men, and 482 (12.0%) had multisource comorbidity scores of 4 or 5. Compared with the maintaining group, patients in the discontinuing group had increased risk of hospital admissions for heart failure (HR, 1.24; 95% CI, 1.07-1.43) and any cardiovascular outcome (HR, 1.14; 95% CI, 1.03-1.26), deaths from any cause (HR, 1.15; 95% CI, 1.02-1.30), and emergency admissions for any cause (HR, 1.12; 95% CI, 1.05-1.19). Conclusions and Relevance In this study of patients receiving polypharmacy, discontinuing statins while maintaining other drug therapies was associated with an increase in the long-term risk of fatal and nonfatal cardiovascular outcomes.

Aims: Women with pre-existing diabetes should plan for optimal care of the disease before, during and after pregnancy. The aim of this study was to assess the quality of diabetes mellitus monitoring and care before, during and after pregnancy in a large cohort of women. Methods: 1913 diabetic women resident in the Lombardy Region (Italy) who experienced at least a birth between 2011 and 2015 and exhibited signs of diabetes ≥2 years before delivery were identified using the healthcare utilization database. Antidiabetic care was defined via outpatient examinations (i.e., assessments of glycated haemoglobin, lipid profile, urine albumin excretion and serum creatinine, and dilated eye exams) and use of antidiabetic drugs. Differences in adherence to recommendations before, during and after pregnancy were assessed by the non-parametric McNemar's test among the whole cohort and among the subgroup with type 1 diabetes. Results: Adherence to recommendations was very poor before pregnancy, ranging from 13% to 42% for dilated eye and serum creatinine exam, respectively. During pregnancy, a significant portion of women increased adherence to all recommendations (e.g., glycated haemoglobin from 20% to 47%, p-value < 0.001), with the exception of lipid profile control. After pregnancy, adherence dropped to pre-pregnancy levels. A similar trend was observed in the use of antidiabetic drugs. Although women with type 1 diabetes showed better adherence across all periods, the same patterns emerged. Conclusions: Besides an improvement in the indicators of clinical adherence during pregnancy, the management of diabetes among pregnant women remains sub-optimal both before and after the birth.

Objective: To determine whether out-of-hospital healthcare and adverse outcomes are better in stroke patients admitted to a neurology ward compared with those admitted to general wards. Methods: Beneficiaries of the National Health Service from the Italian Lombardy Region who were discharged alive after hospital admission during the year 2009 for ischemic stroke (9776 patients) or intracerebral or subarachnoid hemorrhage (1102 patients) entered into the cohort and were followed until 2012. Exposure of interest was the ward type where inpatients were admitted (neuro vs. general wards). Outcomes were out-of-hospital healthcare (i.e., drug prescriptions, diagnostic procedures, and laboratory clinical evaluations) and adverse clinical outcomes (i.e., all-cause death and hospital readmission). Exposure-outcome associations were investigated. High-dimensional propensity score methodology was used for taking into account confounders. Mediation analysis was used to verify whether the association between ward type and clinical outcomes is mediated by out-of-hospital adherence to healthcare. Results: Better adherence to out-of-hospital healthcare received from patients discharged from neuro, rather than general, wards was observed being the proportions of adherent patients 42.4% and 39.5%, respectively. Compared with general wards, discharge from neuro was associated with reduced 3-year emergency admissions (from 50.1 to 47.5% among ischemic stroke patients) and reduced 3-year mortality (from 37.5 to 27.0% among hemorrhagic stroke patients). From 10 to 15% of outcome risk, reductions were mediated by better adherence to out-of-hospital healthcare. Conclusions: For patients with acute ischemic and hemorrhagic stroke, admission to neuro vs. general wards is associated with better out-of-hospital healthcare and long-term adverse outcomes.

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.

Background Incidence and prognostic impact of heart failure (HF) progression has been not well addressed. Methods From 2009 until 2015, consecutive ambulatory HF patients were recruited. HF progression was defined by the presence of at least two of the following criteria: step up of ≥1 New York Heart Association (NYHA) class; decrease LVEF ≥ 10 points; association of diuretics or increase ≥ 50% of furosemide dosage, or HF hospitalization. Results 2528 met study criteria (mean age 76; 42% women). Of these, 48% had ischemic heart disease, 18% patients with LVEF ≤ 35%. During a median follow-up of 2.4 years, overall mortality was 31% (95% CI: 29%–33%), whereas rate of HF progression or death was 57% (95% CI: 55%–59%). The 4-year incidence of HF progression was 39% (95% CI: 37%–41%) whereas the competing mortality rate was 18% (95% CI: 16%–19%). Rates of HF progression and death were higher in HF patients with LVEF ≤ 35% vs >35% (HF progression: 42% vs 38%, p = 0.012; death as a competing risk: 22% vs 17%, p = 0.002). HF progression identified HF patients with a worse survival (HR = 3.16, 95% CI: 2.75–3.72). In cause-specific Cox models, age, previous HF hospitalization, chronic obstructive pulmonary disease, chronic kidney disease, anemia, sex, LVEF ≤ 35% emerged as prognostic factors of HF progression. Conclusions Among outpatients with HF, at 4 years 39% presented a HF progression, while 18% died before any sign of HF progression. This trend was higher in patients with LVEF ≤ 35%. These findings may have implications for healthcare planning and resource allocation.

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.

OBJECTIVES: Minimally invasive techniques seem to be promising alternatives to open approaches in the surgical treatment of early-stage thymoma, although there are controversies because of lack of data on long-term results. The aim of the study was to evaluate the surgical and oncological results after robotic thymectomy for early-stage thymoma compared to median sternotomy. METHODS: Between 1982 and 2017, 164 patients with early-stage thymoma (Masaoka I and II) were operated on by median sternotomy (108 patients) or the robotic approach (56 patients). Duration of surgery, amount of blood loss, complications, duration of chest drainage, postoperative hospital stay, oncological results and total costs were retrospectively evaluated. Data were analysed also after propensity score matching. RESULTS: Compared to the trans-sternal group, robotic thymectomy had significantly longer average operative times (P < 0.001) but less intraoperative blood loss (P = 0.01), less perioperative complications (P = 0.03), shorter time to chest drainage removal and hospital discharge (P < 0.001). The median expense for the trans-sternal approach was significantly higher than the cost of the robotic procedure (P < 0.001), mainly due to longer hospitalization. From an oncological point of view, there were no differences in thymoma recurrence, although follow-up of the trans-sternal group was significantly longer (P < 0.001). Data were confirmed after propensity score matching. CONCLUSIONS: Robotic thymectomy for early-stage thymoma is a technically safe and feasible procedure with low complication rate and shorter hospital stay compared to the trans-sternal approach. Cost analysis revealed lower expenses for the robotic procedure due to the reduced hospital stay. The oncological outcomes seemed comparable, but longer follow-up is needed.

Purpose: The study aimed to fill existing knowledge gaps on the safety of antidepressant drugs (ADs) by estimating the risk of hospitalization for arrhythmia associated with use of selective serotonin reuptake inhibitors (SSRIs) and newer atypical ADs (NAAs) among elderly with previous cardiovascular (CV) events. Methods: The cohort was composed by 199,569 individuals aged ≥ 65 years from five Italian healthcare territorial units who were discharged for cardiovascular outcomes in the years 2008–2010. The 17,277 patients who experienced hospital admission for arrhythmia during follow-up were included as cases. Odds of current ADs use among cases (i.e., 14 days before hospital admission) was compared with (i) odds of current use of 1:5 matched controls (between-patients case-control) and with (ii) odds of previous use during 1:5 matched control periods (within-patient case-crossover). The risk of arrhythmia associated with ADs current use was modelled fitting a conditional logistic regression. A set of sensitivity analyses was performed to account for sources of systematic uncertainty. Results: Current users of SSRIs and NAAs were at increased risk of arrhythmia with case-control odds ratios (OR) of 1.37 (95% confidence interval, CI 1.18 to 1.58) and 1.41 (1.16 to 1.71) and case-crossover OR of 1.48 (1.20 to 1.81) and 1.72 (1.31 to 2.27). An increased risk of arrhythmia was associated with current use of trazodone (NAA) consistently in case-control and case-crossover designs. Conclusions: Evidence that current use of SSRIs and NAAs is associated to an increased risk of arrhythmia among elderly with CV disease was consistently supplied by two observational approaches.

INTRODUCTION: A pathologic grading system (PGS) for malignant pleural mesothelioma (MPM) is warranted to better identify different risk categories of patients, plan therapeutic options, and activate clinical trials. METHODS: A series of 940 patients with MPM (328 in a training set and 612 in a validation set) that was diagnosed between October 1980 and June 2015 at the participant institutions was retrospectively assembled. A PGS was constructed by attributing to each histologic parameter, independent at multivariate analysis with excellent reproducibility (κ > 0.75), different scores based on the increase in corresponding hazard ratios. The relevant PGS score thus ranged from 0 to 8 points for individual patients with MPM. CONCLUSIONS: The PGS was constructed by taking into consideration the histological subtyping of MPM (epithelioid/biphasic = 0 points; sarcomatoid = 2 points), necrosis (absent = 0 points versus present = 1 point), mitotic count per 1 mm2 (cutoffs as follows: 1-2 = 0 points, 3-5 = 1 point, 6-9 = 2 points, or ≥10 = 4 points), and Ki-67 labeling index based on 2000 cells (

Purpose: The aim of this study was to estimate the proportion of bleedings that occurred among warfarin users attributable to the concomitant use of other medications. A general approach for measuring the impact of the prescriptive inappropriateness on drug adverse outcomes at the population level is described. Methods: A meta-analysis was conducted to obtain summary relative risks of bleeding associated with concurrent use of warfarin and other medications compared to warfarin use alone. A population-based investigation was performed, in an Italian cohort of cardiopathic patients aged 65years or older, to estimate the prevalence of concurrent users of warfarin and other medicaments. The population attributable fraction was computed by combining data on summary relative risks and prevalence of concurrent users. Results: Concomitant use of warfarin and cotrimoxazole, amiodarone, quinolones, macrolides, platelet aggregation inhibitors, SSRIs, NSAIDs, and lipid-lowering agents was associated with an increased risk of bleeding. The corresponding attributable fractions were 3% (95% CI 2 to 4%), 21% (1 to 41%), 21% (17 to 25%), 9% (8 to 10%), 14% (12 to 16%), 6% (5 to 8%), 10% (1 to 20%), and 8% (0 to 18%), respectively. Conclusions: More than half of bleeding events occurring among frail elderly using warfarin are attributable to a concomitant use of warfarin with certain drugs. Because some of these drugs appear to be essential for the treatment/prevention of cardiovascular conditions, and their concomitant use with warfarin could be acceptable in some cases, proper INR-monitoring and warfarin dose adjustments are requested.

Objective Scanty data are available on the accuracy of NT-proBNP in the diagnosis of HF and effects of comorbidities in very elderly patients. Methods Symptoms, signs, NT-proBNP, eGFR, Ht, CRP and the presence of cardiomegaly and pleuric effusion were assessed in 895 consecutive patients aged 86 ± 4.3 years admitted to Emergency Department and used to define the diagnosis of HF according to Framingham criteria. Receiver operating characteristic curves (ROC) were used to calculate diagnostic performance and cutoff of NT-proBNP. Sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) were computed for all NT-proBNP cutoffs. Results Satisfactory diagnostic performance was obtained with a lower threshold of 980 pg/mL (Sn 0.95; NPV 0.90) and a higher threshold of 5340 (Sp 0.85; PPV 0.76) but with 42.4% of patients in the uncertainty area. We determined a second couple of cutoffs (1470–4200) that reduced the gray-area to 27.4%, maintaining an acceptable diagnostic performance compared to commonly used cutoffs (300–1800). Ht, CRP and eGFR all correlated with NT-proBNP in groups with and without HF but none affected diagnostic performance. Conclusion NT-proBNP performs satisfactorily for the diagnosis of HF in very elderly patients. Proposed threshold couple, compared with the most used cutoffs, showed a gain in Sp and PPV with a slightly lower performance in Sn and NPV and with a decrease in the gray-area with the second one. Our data do not support the use of different NT-proBNP cutoffs depending on eGFR, Ht and CRP.

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.

Objectives The potential benefit of surgery for malignant pleural mesothelioma (MPM), especially concerning pleurectomy/decortication (P/D), is unclear from the literature. The aim of this study was to evaluate the outcome after multimodality treatment of MPM involving different types of P/D and to analyse the prognostic factors. Methods We reviewed 314 patients affected by MPM who were operated on in 11 Italian centres from 1 January 2007 to 11 October 2014. Results The characteristics of the population were male/female ratio: 3.7/1, and median age at operation was 67.8 years. The epithelioid histotype was observed in 79.9% of patients; neoadjuvant chemotherapy was given to 57% of patients and Stage III disease was found following a pathological analysis in 62.3% of cases. A total of 162 (51.6%) patients underwent extended P/D (EP/D); 115 (36.6%) patients had P/D and 37 (11.8%) received only a partial pleurectomy. Adjuvant radiotherapy was delivered in 39.2% of patients. Median overall survival time after surgery was 23.0 [95% confidence interval (CI): 19.6-29.1] months. On multivariable (Cox) analysis, pathological Stage III-IV [ P = 0.004, hazard ratio (HR):1.34; 95% CI: 1.09-1.64], EP/D and P/D ( P = 0.006, HR for EP/D: 0.46; 95% CI: 0.29-0.74; HR for P/D: 0.52; 95% CI: 0.31-0.87), left-sided disease ( P = 0.01, HR: 1.52; 95% CI: 1.09-2.12) and pathological status T4 ( P = 0.0003, HR: 1.38; 95% CI: 1.14-1.66) were found to be independent significant predictors of overall survival. Conclusions Whether the P/D is extended or not, it shows similarly good outcomes in terms of early results and survival rate. In contrast, a partial pleurectomy, which leaves gross tumour behind, has no impact on survival.

Background Patients with acute heart failure (AHF) have high rates of attendance to emergency departments (EDs), with significant health care costs. Objectives We aimed to describe the clinical characteristics of patients attending Italian EDs for AHF and their diagnostic and therapeutic work-up. Methods We carried out a retrospective analysis on 2683 cases observed in six Italian EDs for AHF (January 2011 to June 2012). Results The median age of patients was 84 years (interquartile range 12), with females accounting for 55.8% of cases (95% confidence interval [CI] 53.5–57.6%). A first episode of AHF was recorded in 55.3% (95% CI 55.4–57.2%). Respiratory disease was the main precipitating factor (approximately 30% of cases), and multiple comorbidities were recorded in > 50% of cases (history of acute coronary syndrome, chronic obstructive pulmonary disease, diabetes, chronic kidney disease, valvular heart disease). The treatment was based on oxygen (69.7%; 67.9–71.5%), diuretics (69.2%; 67.9–71.5%), nitroglycerin (19.7%; 18.3–21.4%), and noninvasive ventilation (15.2%; 13.8–16.6%). Death occurred within 6 h in 2.5% of cases (2.0–3.1%), 6.4% (5.5–7.3%) were referred to the care of their general practitioners within a few hours from ED attendance or after short-term (< 24 h) observation 13.9% (12.6–15.2%); 60.4% (58.5–62.2%) were admitted to the hospital, and 16.8% (15.4–18.3%) were cared for in intensive care units according to disease severity. Conclusions Our study reporting the “real-world” clinical activity indicates that subjects attending the Italian EDs for AHF are rather different from those reported in international registries. Subjects are older, with a higher proportion of females, and high prevalence of cardiac and noncardiac comorbidities.

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