Protective Effects of Home T2DM Treatment with Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Co-transporter-2 Inhibitors Against Intensive Care Unit Admission and Mortality in the Acute Phase of the COVID-19 Pandemic: A Retrospective Observational Study in Italy.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a relevant risk factor for severe forms of COVID-19 (SARS coronavrus 2 [SARS-CoV-2] disease 2019), and calls for caution because of the high prevalence of T2DM worldwide and the high mortality rates observed in patients with T2DM who are infected with SARS-CoV-2. People with T2DM often take dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1ras), or sodium-glucose co-transporter-2 inhibitors (SGLT-2is), all of which have clear anti-inflammatory effects. The study aimed to compare (i) the severity and duration of hospital stay between patients with T2DM categorized by pre-hospitalization drug class utilization and (ii) the COVID-19-related death rates of those three groups. METHODS: We designed an observational, retrospective, multi-center, population-based study and extracted the hospital admission data from the health care records of 1916 T2DM patients over 18 years old who were previously on GLP-1ra, SGLT-2i, or DPP-4i monotherapy and were hospitalized for COVID-19 (diagnosis based on ICD.9/10 codes) between January 2020 and December 2021 in 14 hospitals throughout Italy. We analyzed general data, pre-admission treatment schedules, date of admission or transfer to the intensive care unit (ICU) (i.e., the index date; taken as a marker of increased COVID-19 disease severity), and death (if it had occurred). Statistics analyzed the impact of drug classes on in-hospital mortality using propensity score logistic regressions for (i) those admitted to intensive care and (ii) those not admitted to intensive care, with a random match procedure used to generate a 1:1 comparison without diabetes cohort replacement for each drug therapy group by applying the nearest neighbor method. After propensity score matching, we checked the balance achieved across selected variables if a balance was ever achieved. We then used propensity score matching between the three drug classes to assemble a sample in which each patient receiving an SGLT-2i was matched to one on a GLP-1ra, and each patient on a DPP-4i was matched to one on a GLP-1ra, adjusting for covariates. We finally used GLP-1ras as references in the logistic regression. RESULTS: The overall mortality rate (MR) of the patients was 14.29%. The MR in patients with COVID was 53.62%, and it was as high as 42.42% in the case of associated T2DM, regardless of any glucose-lowering therapy. In those on DPP-4is, there was excess mortality; in those treated with GLP-1ras and SGLT-2is, the death rate was significantly lower, i.e., almost a quarter of the overall mortality observed in COVID-19 patients with T2DM. Indeed, the odds ratio (OR) in the logistic regression resulted in an extremely high risk of in-hospital death in individuals previously treated with DPP-4is [incidence rate (IR) 4.02, 95% confidence interval (CI) 2.2-5.7) and only a slight, nonsignificantly higher risk in those previously treated with SGLT-2is (IR 1.42, 95% CI 0.6-2.1) compared to those on GLP-1ras. Moreover, the longer the stay, the higher the death rate, which ranged from 22.3% for ≤ 3-day stays to 40.3% for 4- to 14-day stays (p < 0.01 vs. the former) and 77.4% for over-14-day stays (p < 0.001 vs. both the others). DISCUSSION: Our data do not support a protective role of DPP-4is; indeed, this role has already been questioned due to previous observations. However, the data do show a strong protective effect of SGLT-2is and GLP-1ras. Beyond lowering circulating glucose levels, those two drug classes were found to exert marked anti-phlogistic effects: SGLT-2is increased adiponectin and reduced urate, leptin, and insulin concentrations, thus positively affecting overall low-grade inflammation, and GLP-1ras may also greatly help at the lung tissue level, meaning that their extra-glycemic effects extend well beyond those acknowledged in the cardiovascular and renal fields. CONCLUSIONS: The aforedescribed observational clinical data relating to a population of Italian inpatients with T2DM suggest that GLP-1ras and SGLT-2is can be considered antidiabetic drugs of choice against COVID-19, and might even prove beneficial in the event of any upcoming pandemic that has life-threatening effects on the pulmonary and cardiovascular systems.

Developing and validating an algorithm to identify incident chronic dialysis patients using administrative data.

BACKGROUND: Administrative healthcare databases are widespread and are often standardized with regard to their content and data coding, thus they can be used also as data sources for surveillance and epidemiological research. Chronic dialysis requires patients to frequently access hospital and clinic services, causing a heavy burden to healthcare providers. This also means that these patients are routinely tracked on administrative databases, yet very few case definitions for their identification are currently available. The aim of this study was to develop two algorithms derived from administrative data for identifying incident chronic dialysis patients and test their validity compared to the reference standard of the regional dialysis registry. METHODS: The algorithms are based on data retrieved from hospital discharge records (HDR) and ambulatory specialty visits (ASV) to identify incident chronic dialysis patients in an Italian region. Subjects are included if they have at least one event in the HDR or ASV databases based on the ICD9-CM dialysis-related diagnosis or procedure codes in the study period. Exclusion criteria comprise non-residents, prevalent cases, or patients undergoing temporary dialysis, and are evaluated only on ASV data by the first algorithm, on both ASV and HDR data by the second algorithm. We validated the algorithms against the Emilia-Romagna regional dialysis registry by searching for incident patients in 2014 and performed sensitivity analyses by modifying the criteria to define temporary dialysis. RESULTS: Algorithm 1 identified 680 patients and algorithm 2 identified 676 initiating dialysis in 2014, compared to 625 patients included in the regional dialysis registry. Sensitivity for the two algorithms was respectively 90.8 and 88.4%, positive predictive value 84.0 and 82.0%, and percentage agreement was 77.4 and 74.1%. CONCLUSIONS: Algorithms relying on retrieval of administrative records have high sensitivity and positive predictive value for the identification of incident chronic dialysis patients. Algorithm 1, which showed the higher accuracy and has a simpler case definition, can be used in place of regional dialysis registries when they are not present or sufficiently developed in a region, or to improve the accuracy and timeliness of existing registries.

Dementia Improvement after Primary Hyperparathyroidism Surgery.

This is the case of a 76-year-old man admitted to hospital in a delirium state, previously diagnosed with a major depressive disorder at an age of 50 years, treated for years for chronic tension headache. The computed tomography of the head resulted negative. Inpatient laboratory tests revealed a mild hypercalcemia. Due to the progression of the disease (delirium state, dementia, tension headache, and depression), he was again admitted to hospital. The patient showed dysarthria, postural tremors, mirror movements and palmar hyperhidrosis, mild ataxia when walking, and rigidity. Sleep disturbances were also observed. He underwent several clinical diagnostic tests, which resulted negative. After more than 2 years, the ultrasound of the neck identified enlarged parathyroid glands. The patient was surgically treated, and three parathyroid glands were removed. Parathyroidectomy and lithium treatment resulted in improvement of cognitive functions. In elderly patients, concomitant presence of cognitive dysfunction may mask the underlying primary hyperparathyroidism.

Proportional incidence of interval colorectal cancer in a large population-based faecal immunochemical test screening programme.

BACKGROUND: The European guidelines for quality assurance in colorectal cancer (CRC) screening recommend that interval cancer rate be expressed as a proportion of background incidence rate. AIM: To determine the crude and adjusted proportional incidence of interval CRC in an Italian regional two-yearly faecal immunochemical test (FIT) screening programme. METHODS: The programme (year of implementation, 2005) is targeted at over 1,000,000 people aged 50-69 years. The test is a one-sample OC-Sensor (Eiken Chemical Co., Tokyo, Japan). The study covered one-third of the regional area. Excerpts of 434,295 eligible negative FIT records dated 2005-2012 from 193,193 subjects were retrieved from the regional CRC screening data warehouse. By 31 December 2013, the cohort accumulated 198,302 man-years and 235,370 woman-years. Interval CRCs were identified by record-linkage with the local population-based cancer registry. Their number was divided by the expected number, estimated with age-period-cohort models, to obtain the proportional incidence. RESULTS: The proportional incidence of interval CRC for men and women was, respectively, 0.06 (95% confidence interval (CI), 0.04-0.09) and 0.17 (95% CI, 0.13-0.23) in the first interval year, and 0.21 (95% CI, 0.16-0.26) and 0.28 (95% CI, 0.22-0.36) in the second year. CONCLUSIONS: The results were acceptable and in line with previous studies.

One-year mortality associated with COPD treatment: a comparison of tiotropium and long-acting beta2-agonists in three Italian regions: results from the OUTPUL study.

PURPOSE: Long-acting bronchodilators, i.e. beta-2-agonists (LABA) and tiotropium are commonly used in COPD treatment. Choice of a specific agent is based on effectiveness and safety. Evidence yields controversial results with respect to mortality. The present study compared one-year mortality associated to treatment with tiotropium versus LABA. METHODS: A population-based cohort study using data from Italian health information systems was performed. Patients aged 45+ years, discharged with COPD diagnosis in 2006-2009 were identified. Through record linkage with drug claims, patients who received a first prescription of LABA or tiotropium within 6 months after discharge were enrolled. The main analysis was restricted to naïve users (no prior use of either LABA or tiotropium). We used 'intention to treat' (ITT) and 'as treated' (AT) approaches. We followed patients for a maximum of 12 months. Hazard ratios (HRs) were calculated by Cox regression including quintiles of propensity score. In sensitivity analysis patients receiving tiotropium + LABA combination were included in the tiotropium group. RESULTS: Among the 33 891 enrolees, 28% were exposed to Tio, 56% to LABA, 16% to both. Overall mean age was 74 years and the mortality rate was 122/1000 person-years (py) at the ITT analysis and 108/1000 py at the AT analysis. The adjusted HR for tiotropium only compared with LABA only was 1.06 (95%CI: 0.94-1.20) at the ITT analysis and 1.00 (95%CI: 0.93-1.08) at the AT analysis. Results were robust in sensitivity analysis. CONCLUSIONS: In this real-world study use of tiotropium was not associated with an increased risk of one-year mortality compared with LABA. © 2016 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.

The Effect on Total Mortality of Adding Inhaled Corticosteroids to Long-Acting Bronchodilators for COPD: A Real Practice Analysis in Italy.

PURPOSE: Chronic therapy with long-acting bronchodilators (LB) is recommended to treat moderate-to-severe COPD. Although the benefits of adding inhaled corticosteroid (ICS) to LB are still unclear, patients who experience repeated exacerbations are suggested to add ICS to their LB treatment. The objective of this study is to analyze whether adding ICS to LB therapy reduces mortality. METHODS: We identified a cohort of patients discharged from hospital with COPD diagnosis between 2006 and 2009. The first prescription for LB or ICS following discharge was defined as the index prescription. Only new users were included (no use of any study drug in the 6 months before treatment). A 4-day time window was used to classify patients into "LB alone" or "LB plus ICS" initiators. We used propensity score to balance the study groups. Sensitivity analyses were performed in patients with recent out-of-hospital exacerbations. RESULTS: Among the 18615 adults enrolled, 12207 initiated "LB plus ICS" therapy and 6408 "LB alone." Crude mortality rates were 110 and 143 cases per 1000 person-years in the "LB plus ICS" and "LB alone" groups, respectively. The adjusted hazard ratio (HR) was 0.83 (95% CI: 0.72-0.97; p-value: 0.024). When analyzing patients with recent out-of-hospital exacerbations, the benefit of the combination therapy was more pronounced, HR = 0.63 (95% CI: 0.44-0.90; p-value: 0.012). DISCUSSION: Our findings showed a beneficial effect on mortality of adding inhaled corticosteroids to long-acting bronchodilators. The advantage was much more pronounced in patients with frequent exacerbations.

Long term effectiveness on prescribing of two multifaceted educational interventions: results of two large scale randomized cluster trials.

INTRODUCTION: Information on benefits and risks of drugs is a key element affecting doctors' prescribing decisions. Outreach visits promoting independent information have proved moderately effective in changing prescribing behaviours. OBJECTIVES: Testing the short and long-term effectiveness on general practitioners' prescribing of small groups meetings led by pharmacists. METHODS: Two cluster open randomised controlled trials (RCTs) were carried out in a large scale NHS setting. Ad hoc prepared evidence based material were used considering a therapeutic area approach--TEA, with information materials on osteoporosis or prostatic hyperplasia--and a single drug oriented approach--SIDRO, with information materials on me-too drugs of 2 different classes: barnidipine or prulifloxacin. In each study, all 115 Primary Care Groups in a Northern Italy area (2.2 million inhabitants, 1737 general practitioners) were randomised to educational small groups meetings, in which available evidence was provided together with drug utilization data and clinical scenarios. Main outcomes were changes in the six-months prescription of targeted drugs. Longer term results (24 and 48 months) were also evaluated. RESULTS: In the TEA trial, one of the four primary outcomes showed a reduction (prescription of alfuzosin compared to tamsulosin and terazosin in benign prostatic hyperplasia: prescribing ratio -8.5%, p = 0.03). Another primary outcome (prescription of risedronate) showed a reduction at 24 and 48 months (-7.6%, p = 0.02; and -9,8%, p = 0.03), but not at six months (-5.1%, p = 0.36). In the SIDRO trial both primary outcomes showed a statistically significant reduction (prescription of barnidipine -9.8%, p = 0.02; prescription of prulifloxacin -11.1%, p = 0.04), which persisted or increased over time. INTERPRETATION: These two cluster RCTs showed the large scale feasibility of a complex educational program in a NHS setting, and its potentially relevant long-term impact on prescribing habits, in particular when focusing on a single drug. National Health systems should invest in independent drug information programs. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN05866587.

Baby-friendly hospitals and cesarean section rate: a survey of Italian hospitals.

BACKGROUND: The Baby-Friendly Hospital Initiative aims at protecting, promoting, and supporting breastfeeding. Cesarean section is known to represent an obstacle to breastfeeding. In this observational study we compared Baby-Friendly and non-Baby-Friendly hospitals (BFHs and non-BFHs, respectively) in terms of cesarean section rate. MATERIALS AND METHODS: Italian BFHs were compared with non-BFHs located in the same regions. Data used for analysis were type of hospital, annual deliveries, annual cesarean section deliveries, region of location, and BFH status. The primary outcome was a cesarean section rate below a threshold specific for the identified regions; because of skewed distribution, the median rate was chosen. Descriptive and comparative univariate and multivariate analyses were carried out. RESULTS: In 2009, in Italy, there were 20 BFHs located in eight regions. Compared with the 207 non-BFHs with more than 200 annual deliveries located in the same regions, BFHs had a cesarean section rate below the median of the eight regions (30.4%; interquartile range 14.6%), even after adjustment for confounders (adjusted odds ratio, 12.71; 95% confidence interval, 1.84, 87.72). In addition, being a public hospital, performing a higher number of deliveries, and being located in specific regions also predicted a cesarean section rate below the median. Overall, the regions with at least one BFH showed a lower cesarean section rate, compared with regions without BFHs. DISCUSSION: In Italy there are few BFHs, but regions with at least one BFH show a cesarean section rate below the national median. Several factors impact on the cesarean section rate, causing huge variation among regions. Nevertheless, within the same region, BFHs have a lower cesarean section rate compared with non-BFHs.

A population based cohort study to assess the safety of pandemic influenza vaccine Focetria in Emilia-Romagna region, Italy - part two.

INTRODUCTION: A two phases post authorization safety and effectiveness study of individuals vaccinated with the MF59-adjuvanted A/H1N1 influenza vaccine, Focetria (Novartis Vaccines & Diagnostics, Siena, Italy), was conducted in Emilia-Romagna region, Italy during the 2009 A/H1N1 influenza pandemic. The second phase study aim was to detect short- and long-term adverse events of special interest (AESIs) following vaccination, and to measure vaccine effectiveness in term of hospital admissions. STUDY DESIGN AND METHOD: A population-based cohort study using record linkage of automated healthcare databases is described. Focetria was administered to 127,522 subjects between October 2009 and February 2010. Vaccinated subjects were generally less healthy than unvaccinated ones. Propensity to be vaccinated was calculated for each subject, and vaccinated and unvaccinated subjects were matched accordingly (103,642 subjects in each group). AESIs were validated against clinical records. RESULTS: In the overall (pre-matching) cohort, a total of 504 short-term incident AESIs (28 in 127,522 vaccinated and 476 in 3,967,917 unvaccinated subjects) were registered (unadjusted OR: 1.8; 95% CI: 1.2, 2.7). No fatalities were recorded. In the matched cohort, a total of 26 short-term incident AESIs (11 in the vaccinated and 15 in the unvaccinated group) were registered, with no differences between groups (OR: 0.7; 95% CI: 0.3, 1.6). Most frequent short-term incident AESIs were convulsions (4 out of 11), and demyelinating diseases (3 out of 11). In the long-term a total of 121 incident AESIs (60 in the vaccinated and 61 in the unvaccinated group) were registered, with no differences between groups (OR: 1.0; 95% CI: 0.7, 1.4). Most common long-term incident AESIs were demyelinating diseases (21 out of 60), and vasculitis (13 out of 60). Vaccine effectiveness was not assessed as the majority of subjects were vaccinated at the end of the pandemic peak and few cases (<0.1%) had laboratory confirmation. CONCLUSIONS: This population-based cohort study using automated databases suggests that Focetria is not associated with an increase in AESIs.

Randomised controlled trials for evaluating the prescribing impact of information meetings led by pharmacists and of new information formats, in General Practice in Italy.

BACKGROUND: Suboptimal translation of valid and relevant information in clinical practice is a problem for all health systems. Lack of information independent from commercial influences, limited efforts to actively implement evidence-based information and its limited comprehensibility are important determinants of this gap and may influence an excessive variability in physicians' prescriptions. This is quite noticeable in Italy, where the philosophy and methods of Evidence-Based Medicine still enjoy limited diffusion among practitioners. Academic detailing and pharmacist outreach visits are interventions of proven efficacy to make independent and evidence-based information available to physicians; this approach and its feasibility have not yet been tested on a large scale and, moreover, they have never been formally tested in Italy. METHODS/DESIGN: Two RCTs are planned:1) a two-arm cluster RCT, carried out in Emilia-Romagna and Friuli Venezia Giulia, will evaluate the effectiveness of small group meetings, randomising about 150 Primary Care Groups (corresponding to about 2000 GPs) to pharmacist outreach visits on two different topics. Physicians' prescriptions (expressed as DDD per 1000 inhabitants/day), knowledge and attitudes (evaluated through the answers to a specific questionnaire) will be compared for target drugs in the two groups (receiving/not receiving each topic).2) A three-arm RCT, carried out in Sardinia, will evaluate both the effectiveness of one-to-one meetings (one pharmacist visiting one physician per time) and of a 'new' information format (compared to information already available) on changing physicians' prescription of specific drugs. About 900 single GPs will be randomised into three groups: physicians receiving a visit supported by "traditional" information material, those receiving a visit with "new" information material on the same topic and those not receiving any visit/material. DISCUSSION: The two proposed RCTs aim to evaluate the organisational feasibility and barriers to the implementation of independent information programs led by NHS pharmacists. The objective to assess a 10 or 15% decreases in the prescription of the targeted drugs is quite ambitious in such 'natural' settings, which will be minimally altered by the interventions themselves; this in spite of the quite large sample sizes used comparing to other studies of these kind. Complex interventions like these are not easy to evaluate, given the many different variables into play. Anyway, the pragmatic nature of the two RCTs appears to be also one of their major strengths, helping to provide a deeper insight on what is possible to achieve - in terms of independent information - in a National Health System, with special reference to Italy. TRIAL REGISTRATION: ISRCTN05866587 (cluster RCT) and ISRCTN28525676 (single GPs RCT).

Do coxibs reduce prescription of gastroprotective agents? Results of a record linkage study.

BACKGROUND: Coxibs are claimed to be cost-effective drugs and reduced prescription of gastroprotective agents is assumed to be one of their major benefits. Real life prescription of these drugs may be substantially different than that considered in pharmacoeconomic analyses or claimed by drug companies, yet. Our objective was to evaluate whether coxibs were associated with reduced prescription of gastro-protective agents (GPAs, specifically proton pump inhibitors, H2 blockers and misoprostol) compared to non selective NSAIDs. METHODS: A record-linkage study was performed using 2001 outpatient prescription data from the province of Modena (about 632,000 inhabitants, in Northern Italy). Logistic regression was used to calculate the odds ratio of GPA prescription for coxib and non-selective NSAID adult users (> 14 years). Three categories of users were further investigated: "acute", "chronic and "incident or new". Main outcome measures were same-day co-prescription and 30 days prescription of GPAs in coxibs and non selective NSAIDs users. To limit selection bias, data were adjusted for age, sex, DDD of coxibs and non selective NSAIDs received during 2001, DDD of GPAs and (for non-incident users) DDD of NSAIDs received during the previous 4 years RESULTS: Same day co-prescription rates were similar considering the overall population and "acute" users. Chronic coxibs users instead showed higher co-prescription rates than chronic NSAIDs users (OR = 1.2, p < 0.05). GPA prescription within thirty days was also higher among all subgroups of coxibs users (OR ranging from 1.6 to 2.0, p < 0.001). CONCLUSION: Assumptions made in pharmacoeconomic analyses on coxibs (lower GPA prescription associated with coxibs use) may be overly optimistic. Claims made through cost-effectiveness data should be carefully interpreted, and mechanisms for attributing drug prices revised accordingly.

Liver transplantation for hepatocellular carcinoma: further considerations on selection criteria.

The selection criteria in liver transplantation for HCC are a matter of debate. We reviewed our series, comparing two periods: before and after 1996, when we started to apply the Milan criteria. The study population was composed of patients with a preoperative diagnosis of HCC, confirmed by the pathological report and with a survival of >1 year. Preoperative staging as revealed by radiological imagining was distinguished from postoperative data, including the variable of tumor volume. After 1996 tumor recurrences significantly decreased (6 out of 15 cases, 40% vs. 3 out of 48, 6.3%, P < .005) and 5-year patient survival improved (42% vs. 83%, P < .005). Not meeting the Milan criteria was significantly related to higher recurrence rate (37.5% vs. 12.7%, P < .05) and to lower 5-year patient survival (38% vs. 78%, P < .005%) in the preoperative analysis, but not in the postoperative one. The alfa-fetoprotein level of more than 30 ng/dL and the preoperative tumor volume of more than 28 cm3 predicted HCC recurrences in the univariate and mutivariate analysis (P < .005 and P < .05, respectively). The ROC curve showed a linear correlation between preoperative tumor volume and HCC recurrence. Milan criteria significantly reduced tumor recurrences after liver transplantation, improving long-term survival. In conclusion, the efficacy of tumor selection criteria must be analyzed with the use of preoperative data, to avoid bias of the postoperative evaluation. Tumor volume and alfa-fetoprotein level may improve the selection of patients.