Vaccino antinfluenzale stagionale in Italia: misurare l’efficacia sul campo e la sicurezza : Stagione 2015-2016

In Italia, nella stagione influenzale 2015-2016 sono stati condotti dall\u2019Istituto Superiore di Sanit\ue0 (ISS), con il supporto dell\u2019Agenzia Italiana del Farmaco (AIFA), due studi al fine di stimare l\u2019efficacia sul campo (I-MOVE, Influenza - Monitoring Vaccine Effectiveness) e valutare la sicurezza (SVEVA, Studio sulla Valutazione degli Eventi dopo Vaccinazione Antinfluenzale) del vaccino antinfluenzale. Nel complesso hanno aderito 8 Regioni che corrispondono a oltre met\ue0 della popolazione italiana nel 2015 (non tutte le Regioni hanno aderito a entrambi gli obiettivi di studio). Nello studio I-MOVE sono stati reclutati 1.094 casi di ILI (Influenza-Like Illness), dai 64 medici di medicina generale e pediatri di libera scelta partecipanti (506 casi e 498 controlli). I risultati suggeriscono che il vaccino ha conferito una protezione moderata nei confronti del tipo virale A(H1N1)pdm09 e molto bassa per A(H3N2) e B a causa del sostanziale grado di mismatch antigenico osservato, rispetto al ceppo vaccinale. Nello studio SVEVA sono stati monitorati 3.213 soggetti vaccinati e rilevati 854 (26%) eventi dopo 7 giorni dalla vaccinazione, la maggior parte dei quali di lieve entit\ue0. Al fine di ottenere stime di efficacia pi\uf9 solide e descrivere eventi avversi rari, \ue8 necessario tuttavia raggiungere una numerosit\ue0 campionaria maggiore.In Italy, during the 2015/2016 flu season, the National Institute of Health (ISS), with the support of the Italian Drug Agency (AIFA), conducted two studies to estimate vaccine effectiveness (I-MOVE) and evaluate safety (SVEVA) of the flu vaccine. A total of 8 regions, among 21, participated to the study which can correspond to more than 50% of the Italian population in 2015 (not all regions participated to both objectives of the study). For the I-MOVE study, 1094 cases of ILI (506 cases and 498 controls) were recruited by 64 general practitioners and pediatricians. The results indicate that the vaccine gave moderate protection against the virus type A (H1N1) pdm09 and very low protection for A (H3N2) and B due to the antigenic mismatch that was observed, compared to the vaccine strain. For SVEVA study, 3213 vaccinated cases were monitored and 854 (26%) side effects were notified after 7 days of vaccination, the major part were mild. In order to obtain more solid data regarding vaccine effectiveness, and to describe rare adverse events, it is necessary to increase the sample size of both studies

Broad Spectrum project: Factors determining the quality of antibiotic use in primary care: An observational study protocol from Italy

Introduction The overuse of antibiotics is causing worldwide spread of antimicrobial resistance (AMR). Compared with other countries, Italy has both high antibiotic consumption rates and high rates of AMR. Due to the fact that around 90% of antibiotics are prescribed by general practitioners (GPs), this study aims to measure the impact of knowledge, attitudes and sociodemographic and workplace-related factors on the quality of antibiotic prescriptions filled by GPs in the Italian Region of Sardinia. Methods and analysis Knowledge, attitude, sociodemographic and workplace-related factors deemed to influence physicians prescribing behaviour will be evaluated in a cross-sectional study conducted among all GPs of the Italian Region of Sardinia (n=1200). A knowledge and attitudes questionnaire (Knowledge and Attitudes on Antibiotics and Resistance - Italian version: ITA-KAAR) accompanied by a sociodemographic form will be linked to drug prescription data reimbursed by the National Health System. European Surveillance of Antibiotic Consumption quality indicators for outpatient antibiotic use will be calculated from drug prescription records. Every GP will be deemed to have demonstrated an adequate quality of prescriptions of antibiotics if half of the indicator score plus one is better than the median of the region. A multivariate Poisson regression model with robust variance estimation will be used to evaluate the impact of the determinants of antibiotic prescriptions on the actual prescribing quality of each physician. Ethics and dissemination The project has been approved by the ethics committee of the Regional Health Trust of Sardinia (176/2019/CE, 24 September 2019). The results will be useful to inform evidence-based interventions to tackle irrational antibiotic use in the community

Risk of SARS-CoV-2 infection and subsequent hospital admission and death at different time intervals since first dose of COVID-19 vaccine administration, Italy, 27 December 2020 to mid-April 2021

To assess the real-world impact of vaccines on COVID-19 related outcomes, we analysed data from over 7 million recipients of at least one COVID-19 vaccine dose in Italy. Taking 0–14 days post-first dose as reference, the SARS-CoV-2 infection risk subsequently decreased, reaching a reduction by 78% (incidence rate ratios (IRR): 0.22; 95% CI: 0.21–0.24) 43–49 days post-first dose. Similarly, hospitalisation and death risks decreased, with 89% (IRR: 0.11; 95% CI: 0.09–0.15) and 93% (IRR: 0.07; 95% CI: 0.04–0.11) reductions 36–42 days post-first dose. Our results support ongoing vaccination campaigns

Time to Treatment Intensification in Patients Receiving DPP4 Inhibitors Versus Sulfonylureas as the First Add-On to Metformin Monotherapy: A Retrospective Cohort Study

Background: To verify whether, in patients on metformin (MET) monotherapy for type 2 diabetes (T2D), the add-on of a dipeptidyl peptidase inhibitor (DPP4i) compared to a sulfonylurea (SU) can delay the time to the subsequent treatment intensification (TI). Methods: Population-based administrative data banks from four Italian geographic areas were used. Patients aged ≥18 years on MET monotherapy receiving first DPP4i or SU dispensing between 2008 and 2015 (cohort entry) were followed up to the occurrence of TI (insulin dispensing or add-on of a third non-insulin hypoglicemic >180 days after cohort entry), treatment discontinuation, switch, cancer, death, TI occurrence within, end of data availability, end of study period (31 December 2016), whichever came first. Patients on MET + DPP4i were matched 1:1 with those on MET + SU by sex, age, year of cohort entry, and data bank. Hazard Ratio (HR) and 95% confidence intervals (95%CI) were estimated using multivariable Cox regression model including matching variables and potential confounders measured at baseline. Different sensitivity analyses were performed: i) matching at 180 days after cohort entry, ii) intent to treat (ITT) analysis, iii) matching by duration of MET monotherapy, iv) matching by propensity score. Results: The matched study cohort included 10,600 patients. Overall, 763 TI were observed (4.5/100 person-years; mean follow-up = 1.6 years). The primary analysis showed no difference in time to TI between the two groups (HR = 1.02; 95% CI = 0.88–1.19). Sensitivity analyses confirmed this result, except from the ITT analysis (HR = 1.27; 1.13–1.43). Conclusion: The use of a DPP4i rather than a SU as add-on to MET monotherapy was not associated with a delay in treatment intensification

Patterns and trends of utilization of incretin-based medicines between 2008 and 2014 in three Italian geographic areas

Background: The incretin-based medicines GLP1 analogues (GLP1a) and dipeptidyl peptidase-4 inhibitors (DPP4i) are hypoglycaemic agents licensed for the treatment of type 2 diabetes mellitus (T2DM). Although these drugs possess comparable efficacy and low risk of hypoglycaemia, differences in terms of route of administration (subcutaneous versus oral), effect on body weight and gastrointestinal tolerabily can impact their actual use in clinical practice. This study aimed to describe the real-world utilization of incretin-based medicines in the Italian clinical practice. Methods: A multi-database, population-based, descriptive, cohort study was performed using administrative data collected between 2008 and 2014 from three Italian geographic areas. Subjects aged 6518 were selected. New users were defined as those with 651 dispensing of GLP1a or DPP4i during the year of interest and none in the past. Trends of cumulative annual incidence of use in the general adult population were observed. New users of GLP1a or DPP4i were respectively described in terms of demographic characteristics and use of antidiabetic drugs during 1 year before and after the first incretin dispensing. Results: The overall study population included 4,943,952 subjects. A total of 7357 new users of GLP1a and 41,907 of DPP4i were identified during the study period. Incidence of use increased between 2008 (0.2\u2030 for both GLP1a and DPP4i) and 2011 (GLP1a = 0.6\u2030; DPP4i = 2.5\u2030) and slightly decreased thereafter. In 2014, 61% of new GLP1a users received once-daily liraglutide while 52% of new DPP4i users received metformin/DPP4i in fixed-dose. The percentage of new DPP4i users older than 65 years of age increased from 30.9 to 62.6% during the study period. Around 12% of new users had not received any antidiabetic before starting an incretin. Conclusions: During the study period, DPP4i rapidly became the most prescribed incretin-based medicine, particularly among older new user. The choice of the specific incretin-based medicine at first prescription appeared to be directed towards those with higher convenience of use (e.g. oral DPP4i rather than subcutaneous GLP1a, once-daily liraglutide rather than twice-daily exenatide). The non-negligibile use of incretin-based medicines as first-line pharmacotherapy for T2DM warrants further effectiveness and safety evaluations to better define their place in therapy

Recurrence of Cardiovascular Events in Patients With Type 2 Diabetes : Epidemiology and risk factors

OBJECTIVE—The purpose of this study was to assess incidence of and risk factors for recurrent cardiovascular disease (CVD) in type 2 diabetes

Effect of High-Titer Convalescent Plasma on Progression to Severe Respiratory Failure or Death in Hospitalized Patients with COVID-19 Pneumonia: A Randomized Clinical Trial

Importance: Convalescent plasma (CP) has been generally unsuccessful in preventing worsening of respiratory failure or death in hospitalized patients with COVID-19 pneumonia. Objective: To evaluate the efficacy of CP plus standard therapy (ST) vs ST alone in preventing worsening respiratory failure or death in patients with COVID-19 pneumonia. Design, Setting, and Participants: This prospective, open-label, randomized clinical trial enrolled (1:1 ratio) hospitalized patients with COVID-19 pneumonia to receive CP plus ST or ST alone between July 15 and December 8, 2020, at 27 clinical sites in Italy. Hospitalized adults with COVID-19 pneumonia and a partial pressure of oxygen-to-fraction of inspired oxygen (Pao2/Fio2) ratio between 350 and 200 mm Hg were eligible. Interventions: Patients in the experimental group received intravenous high-titer CP (≥1:160, by microneutralization test) plus ST. The volume of infused CP was 200 mL given from 1 to a maximum of 3 infusions. Patients in the control group received ST, represented by remdesivir, glucocorticoids, and low-molecular weight heparin, according to the Agenzia Italiana del Farmaco recommendations. Main Outcomes and Measures: The primary outcome was a composite of worsening respiratory failure (Pao2/Fio2ratio <150 mm Hg) or death within 30 days from randomization. Results: Of the 487 randomized patients (241 to CP plus ST; 246 to ST alone), 312 (64.1%) were men; the median (IQR) age was 64 (54.0-74.0) years. The modified intention-to-treat population included 473 patients. The primary end point occurred in 59 of 231 patients (25.5%) treated with CP and ST and in 67 of 239 patients (28.0%) who received ST (odds ratio, 0.88; 95% CI, 0.59-1.33; P =.54). Adverse events occurred more frequently in the CP group (12 of 241 [5.0%]) compared with the control group (4 of 246 [1.6%]; P =.04). Conclusions and Relevance: In patients with moderate to severe COVID-19 pneumonia, high-titer anti-SARS-CoV-2 CP did not reduce the progression to severe respiratory failure or death within 30 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04716556

How Are the Interests of Incapacitated Research Participants Protected through Legislation? An Italian Study on Legal Agency for Dementia Patients

Patients with dementia may have limited capacity to give informed consent to participate in clinical research. One possible way to safeguard the patients' interests in research is the involvement of a proxy in the recruitment process. In Italy, the system of proxy is determined by the courts. In this study we evaluate the timing for appointment of a legal proxy in Italy and identify predictive variables of appointment.Subjects were recruited among the outpatients seeking medical advice for cognitive complaints at the Centre for Research and Treatment of Cognitive Dysfunctions, University of Milan, "Luigi Sacco" Hospital. The Centre was participating to the AdCare Study, a no-profit randomised clinical trial coordinated by the Italian National Institute of Health. The requirement that informed consent be given by a legal representative dramatically slowed down the recruitment process in AdCare, which was prematurely interrupted. The Centre for Research and Treatment of Cognitive Dysfunctions collected data on the timing required to appoint the legal representatives. Patients diagnosed with dementia and their caregivers were provided information on the Italian law on legal agency (law 6/2004). At each scheduled check-up the caregiver was asked whether she/he had applied to appoint a legal proxy for the patient and the time interval between the presentation of the law, the registration of the application at the law court chancellery and the sentence of appointment was registered. The study involved 169 demented patients. Seventy-eight patients (46.2%) applied to appoint a legal proxy. These subjects were usually younger, had been suffering from dementia for a longer time, had less than two children and made more use of memantine. The mean interval time between the presentation of the law and the patients' application to the law court chancellery was two months. The mean interval time between the patient's application to the law court chancellery and the sentence of appointment was four months.In Italy the requirement that legal representatives be appointed by the courts slows down subjects' participation in research. Other procedures for legal agency of the incapacitated patients may be adopted, taking as examples other EU countries' systems

Patterns and trends of utilization of incretin-based medicines between 2008 and 2014 in three Italian geographic areas

Background: The incretin-based medicines GLP1 analogues (GLP1a) and dipeptidyl peptidase-4 inhibitors (DPP4i) are hypoglycaemic agents licensed for the treatment of type 2 diabetes mellitus (T2DM). Although these drugs possess comparable efficacy and low risk of hypoglycaemia, differences in terms of route of administration (subcutaneous versus oral), effect on body weight and gastrointestinal tolerabily can impact their actual use in clinical practice. This study aimed to describe the real-world utilization of incretin-based medicines in the Italian clinical practice. Methods: A multi-database, population-based, descriptive, cohort study was performed using administrative data collected between 2008 and 2014 from three Italian geographic areas. Subjects aged ≥18 were selected. New users were defined as those with ≥1 dispensing of GLP1a or DPP4i during the year of interest and none in the past. Trends of cumulative annual incidence of use in the general adult population were observed. New users of GLP1a or DPP4i were respectively described in terms of demographic characteristics and use of antidiabetic drugs during 1 year before and after the first incretin dispensing. Results: The overall study population included 4,943,952 subjects. A total of 7357 new users of GLP1a and 41,907 of DPP4i were identified during the study period. Incidence of use increased between 2008 (0.2‰ for both GLP1a and DPP4i) and 2011 (GLP1a = 0.6‰; DPP4i = 2.5‰) and slightly decreased thereafter. In 2014, 61% of new GLP1a users received once-daily liraglutide while 52% of new DPP4i users received metformin/DPP4i in fixed-dose. The percentage of new DPP4i users older than 65 years of age increased from 30.9 to 62.6% during the study period. Around 12% of new users had not received any antidiabetic before starting an incretin. Conclusions: During the study period, DPP4i rapidly became the most prescribed incretin-based medicine, particularly among older new user. The choice of the specific incretin-based medicine at first prescription appeared to be directed towards those with higher convenience of use (e.g. oral DPP4i rather than subcutaneous GLP1a, once-daily liraglutide rather than twice-daily exenatide). The non-negligibile use of incretin-based medicines as first-line pharmacotherapy for T2DM warrants further effectiveness and safety evaluations to better define their place in therapy

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0–1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0–2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4–6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10–2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05–1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06–2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4–6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52–1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03–4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22–25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None