Effectiveness and economic impact of Dupilumab in asthma: a population-based cohort study.

RATIONALE: Severe asthma is burdened by relevant socio-economic and clinical impact. Randomized controlled trials on Dupilumab showed efficacy and a good safety profile, but post-market studies are needed. OBJECTIVES: To evaluate the impact of Dupilumab on (i) the use of anti-asthmatic drugs, including oral corticosteroids (OCS), (ii) the rates of asthma exacerbation-related hospital admissions, and (iii) the healthcare costs in patients with asthma. METHODS: Data were retrieved from Healthcare Utilization database of Lombardy region (Italy). We compared healthcare resources use between the 6 months after Dupilumab initiation ("post-intervention period") and (i) the 6 months before Dupilumab initiation ("wash-out period") and (ii) the corresponding 6 months of the prior year ("pre-intervention period"). MAIN RESULTS: In a cohort of 176 patients, Dupilumab significantly reduced anti-asthmatic drugs use (including OCS and short-acting ß2-agonists, inhaled corticosteroids (ICS)/long-acting ß2-agonists and ICS alone) when comparing the "pre-intervention" to the "post-intervention" period. When considering hospital admissions, we observed a not statistically or marginally significant reduction between both periods before Dupilumab and the post-intervention period. Six-months discontinuation rate was 8%. Overall healthcare costs had a tenfold increase between the "pre-intervention" and "post-intervention" period, which was mainly led by the biologic drug cost. Conversely, expenditures connected to hospital admissions did not change. CONCLUSIONS: Our real-world investigation suggests that Dupilumab reduced anti-asthmatic drugs use, including OCS, in comparison to a corresponding period in the prior year. However, long-term healthcare sustainability remains an open issue.

Cost-Effectiveness of Posthospital Management of Acute Coronary Syndrome: A Real-World Investigation From Italy.

OBJECTIVES: This study aimed to assess the cost-effectiveness profile of adherence to recommendations for the community management of patients discharged with a diagnosis of acute coronary syndrome (ACS). METHODS: The cohort of 50 282 residents in the Lombardy Region (Italy) who were discharged with a diagnosis of ACS during 2011 to 2015 was followed up until 2018. Adherence to selected recommendations including drug therapies (DTs), outpatient controls, and rehabilitation, experienced during the first year after index discharge, was considered. Adherent and nonadherent cohort members were matched on high-dimensional propensity scores. Composite clinical outcomes (cardiovascular hospital admissions and all-cause mortality) and healthcare costs were assessed for a time horizon of 5 years. Cost-effectiveness profile of adherence to recommendations was measured through the incremental cost-effectiveness ratio, that is, the incremental cost for 1 day free from the composite clinical outcome. RESULTS: Adherence to DTs, outpatient controls, and rehabilitation, respectively, regarded 39%, 81%, and 3% of cohort members. Compared with nonadherent patients, those adherent to DTs, outpatient controls, and rehabilitation had (1) a delay in the occurrence of the composite clinical outcome of 50, 43, and 73 days, respectively, and (2) lower (on average, €199 per year for DTs) and higher costs (€292 and €1024 for outpatient controls and rehabilitation). Cost-effectiveness profiles were better for patients with myocardial infarction than those with angina and for patients with more severe clinical complexity than those with milder conditions. CONCLUSIONS: Health-related and economic benefits are expected from improving adherence to international guidelines recommendations concerning outpatient treatments and monitoring of patients with ACS.

Is Switching from Oral Antidiabetic Therapy to Insulin Associated with an Increased Fracture Risk?

BACKGROUND: Observational studies showed that exposure to exogenous insulin increases fracture risk. However, it remains unclear whether the observed association is a function of the severity of underlying type 2 diabetes mellitus, complications, therapies, comorbidities, or all these factors combined. That being so, and because of the relative infrequency of these events, it is important to study this further in a large-database setting. QUESTION/PURPOSES: (1) Is switching from oral antidiabetic agents to insulin associated with an increased fracture risk? (2) How soon after switching does the increased risk appear, and for how long does this increased risk persist? METHODS: Data from healthcare utilization databases of the Italian region of Lombardy were used. These healthcare utilization databases report accurate, complete, and interconnectable information of inpatient and outpatient diagnoses, therapies, and services provided to the almost 10 million residents in the region. The 216,624 patients on treatment with oral antidiabetic therapy from 2005 to 2009 were followed until 2010 to identify those who modified their antidiabetic therapy (step 1 cohort). Among the 63% (136,307 patients) who experienced a therapy modification, 21% (28,420 patients) switched to insulin (active exposure), and the remaining 79% (107,887 patients) changed to another oral medication (referent exposure). A 1:1 high-dimension propensity score matching design was adopted for balancing patients on active and referent exposure. Matching failed for 3% of patients (926 patients), so the cohort of interest was formed by 27,494 insulin-referent couples. The latter were followed until 2012 to identify those who experienced hospital admission for fracture (outcome). A Cox proportional hazard model was fitted to estimate the hazard ratio (HR) for the outcome risk associated with active-exposure (first research question). Between-exposure comparison of daily fracture hazard rates from switching until the 24 successive months was explored through the Kernel-smoothed estimator (second research question). RESULTS: Compared with patients on referent exposure, those who switched to insulin had an increased risk of experiencing any fracture (HR = 1.5 [95% CI 1.3 to 1.6]; p < 0.001). The same risk was observed for hip and vertebral fractures, with HRs of 1.6 (95% CI 1.4 to 1.8; p < 0.001) and 1.8 (95% 1.5 to 2.3; p < 0.001), respectively. Differences in the daily pattern of outcome rates mainly appeared the first 2 months after switching, when the hazard rate of patients on active exposure (9 cases for every 100,000 person-days) was higher than that of patients on referent exposure (4 cases for every 100,000 person-days). These differences persisted during the remaining follow-up, though with reduced intensity. CONCLUSIONS: We found quantitative evidence that switching from oral antidiabetic therapy to insulin is associated with an increased fracture risk, mainly in the period immediately after the start of insulin therapy. The observed association may result from higher hypoglycemia risk among patients on insulin, which leads to a greater number of falls and resulting fractures. However, although our study was based on a large sample size and highly accurate data, its observational design and the lack of clinical data suggest that future research will need to replicate or refute our findings and address the issue of causality, if any. Until then, though, prescribers and patients should be aware of this risk. Careful control of insulin dosage should be maintained and measures taken to reduce fall risk in these patients. LEVEL OF EVIDENCE: Level III, therapeutic study.

Translation, cross-cultural adaptation, and validation of the Italian language Forgotten Joint Score-12 (FJS-12) as an outcome measure for total knee arthroplasty in an Italian population.

BACKGROUND: With ever-increasing numbers of patients undergoing elective total knee arthroplasty (TKA) and as TKA is performed in increasingly younger patients, patient demands and expectations have also increased. With improved patient outcomes, new PROMs with heightened discriminatory power in well-performing patients are needed. The present study aimed to translate and validate the Italian version of the Forgotten Joint Score (FJS-12) as a tool for evaluating pre-operative through longitudinal post-operative outcomes in an Italian population. METHODS: In this prospective study, patients with unilateral osteoarthritis, undergoing TKA surgery between May 2015 and December 2017 were recruited to participate in the study. The FJS-12 and WOMAC were collected pre-operatively and at six and 12 months post-operatively. According to the COSMIN checklist, reliability, internal consistency, validity, responsiveness, effect size, and ceiling effects and floor effects were evaluated. RESULTS: One hundred twenty patients completed the study, 66 of which participated in the evaluation of test-retest reliability. Good test-retest reliability was found (ICC = 0.90). The FJS-12 also showed excellent internal consistency (Cronbach α = 0.81). Construct validity with the WOMAC, as a measure of the Pearson correlation coefficient, was moderate (r = 0.45 pre-operatively; r = 0.46 at 6 months and r = 0.42 at 12 months post-operatively). From six to 12 months, the change was slightly greater for the WOMAC than for the FJS-12 patients (effect size d = 0.94; d = 0.75, respectively). At 12-months follow-up, the ceiling effects reflecting the maximum score were 12% for the FJS-12 and 6% for the WOMAC; however, scores within 10% of the maximum score were comprised 30% of the FJS-12 scores and 59% for the WOMAC. CONCLUSION: The Italian FJS-12 demonstrated strong measurement properties in terms of reliability, internal consistency, and construct validity in TKA patients. Furthermore, a more detailed look at ceiling effects shows a superior discriminatory capacity when compared to the WOMAC at 12-months follow-up, particularly in better-performing patients. TRIAL REGISTRATION: clinicaltrials.gov NCT03805490. Registered 18 January 2019 (retrospectively registered).

The sequential antifracturative treatment: a meta-analysis of randomized clinical trials.

Background: Subjects with a fragility fracture have an increased risk of a new fracture and should receive effective strategies to prevent new events. The medium-term to long-term strategy should be scheduled by considering the mechanisms of action in therapy and the estimated fracture risk. Objective: A systematic review was conducted to evaluate the sequential strategy in patients with or at risk of a fragility fracture in the context of the development of the Italian Guidelines. Design: Systematic review and meta-analysis. Data sources and methods: PubMed, Embase, and the Cochrane Library were investigated up to February 2021 to update the search of a recent systematic review. Randomized clinical trials (RCTs) that analyzed the sequential therapy of antiresorptive, anabolic treatment, or placebo in patients with or at risk of a fragility fracture were eligible. Three authors independently extracted data and appraised the risk of bias in the included studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Effect sizes were pooled in a meta-analysis using fixed-effects models. The primary outcome was the risk of refracture, while the secondary outcome was the bone mineral density (BMD) change. Results: In all, 17 RCTs, ranging from low to high quality, met our inclusion criteria. A significantly reduced risk of fracture was detected at (i) 12 or 24 months after the switch from romosozumab to denosumab versus placebo to denosumab; (ii) 30 months from teriparatide to bisphosphonates versus placebo to bisphosphonates; and (iii) 12 months from romosozumab to alendronate versus the only alendronate therapy (specifically for vertebral fractures). In general, at 2 years after the switch from anabolic to antiresorptive drugs, a weighted BMD was increased at the lumbar spine, total hip, and femoral neck site. Conclusion: The Task Force formulated recommendations on sequential therapy, which is the first treatment with anabolic drugs or 'bone builders' in patients with very high or imminent risk of fracture.

A systematic review to evaluate the sequential therapy of antiresorptive (denosumab and bisphosphonate, such as alendronate, minodronate, risedronate, and etidronate), anabolic treatment (such as romosozumab, teriparatide), or placebo in patients with or at risk of a fragility fracture in the context of the development of the Italian Guidelines Subjects with previous fragility fractures should promptly receive effective strategies to prevent the risk of subsequent events. Indeed, patients with a fragility fracture have a doubled risk of a new fracture. For this reason, it is essential to provide adequate sequential therapy based on the mechanisms and the rapidity of action. A systematic review was performed to identify the sequential strategy in patients at high- or imminent-risk of (re)fracture and to support the Panel of the Italian Fragility Fracture Guideline in formulating recommendations. Our systematic review included seventeen studies mostly focused on women and enabled us to strongly recommend the anabolic drugs as first-line treatment. Specifically, for the sequential therapy from anabolic to antiresorptive treatment, there was a significant reduction in the risk of different types of fractures after the switch from romosozumab to denosumab versus placebo to denosumab. These findings were confirmed at 24 months after the switch. Considering the sequential treatment from antiresorptive to anabolic medications, there was a decreased risk of fracture 12 months after the switch from placebo to teriparatide versus bisphosphonate or antiresorptive to teriparatide. Moreover, a greater bone mineral density increase after the switch from anabolic to antiresorptive medications was shown in the lumbar spine, total hip, and femoral neck. The results of this systematic review and meta-analysis confirm that initial treatment with anabolic drugs produces substantial bone mineral density improvements, and the transition to antiresorptive drugs can preserve or even amplify the acquired benefit. These findings support the choice to treat very high-risk individuals with anabolic drugs first, followed by antiresorptive drugs.

Sex-Related Differences in Outpatient Healthcare of Acute Coronary Syndrome: Evidence from an Italian Real-World Investigation.

At the time of first acute coronary syndrome (ACS) hospital admission, women are generally older and have more comorbidities than men, which may explain differences in their short-term prognosis. However, few studies have focused on differences in the out-of-hospital management of men and women. This study investigated (i) the risk of clinical outcomes, (ii) the use of out-of-hospital healthcare and (iii) the effects of clinical recommendations on outcomes in men vs. women. A total of 90,779 residents of the Lombardy Region (Italy) were hospitalized for ACS from 2011 to 2015. Exposure to prescribed drugs, diagnostic procedures, laboratory tests, and cardiac rehabilitation in the first year after ACS hospitalization were recorded. To evaluate whether sex can modify the relationship between clinical recommendations and outcomes, adjusted Cox models were separately fitted for men and women. Women were exposed to fewer treatments, required fewer outpatient services than men and had a lower risk of long-term clinical events. The stratified analysis showed an association between adherence to clinical recommendations and a lower risk of clinical outcomes in both sexes. Since improved adherence to clinical recommendations seems to be beneficial for both sexes, tight out-of-hospital healthcare control should be recommended to achieve favourable clinical benefits.

Healthcare costs and resource utilisation in bronchiectasis, asthma and COPD.

Direct healthcare costs for patients with asthma are less than half (-52%) and for patients with COPD are 41% higher if compared to those of patients with bronchiectasis. The leading expense items in bronchiectasis are hospitalisations and antibiotics. https://bit.ly/3Iq8AUP.

Executive summary: Italian guidelines for diagnosis, risk stratification, and care continuity of fragility fractures 2021.

Background: Fragility fractures are a major public health concern owing to their worrying and growing burden and their onerous burden upon health systems. There is now a substantial body of evidence that individuals who have already suffered a fragility fracture are at a greater risk for further fractures, thus suggesting the potential for secondary prevention in this field. Purpose: This guideline aims to provide evidence-based recommendations for recognizing, stratifying the risk, treating, and managing patients with fragility fracture. This is a summary version of the full Italian guideline. Methods: The Italian Fragility Fracture Team appointed by the Italian National Health Institute was employed from January 2020 to February 2021 to (i) identify previously published systematic reviews and guidelines on the field, (ii) formulate relevant clinical questions, (iii) systematically review literature and summarize evidence, (iv) draft the Evidence to Decision Framework, and (v) formulate recommendations. Results: Overall, 351 original papers were included in our systematic review to answer six clinical questions. Recommendations were categorized into issues concerning (i) frailty recognition as the cause of bone fracture, (ii) (re)fracture risk assessment, for prioritizing interventions, and (iii) treatment and management of patients experiencing fragility fractures. Six recommendations were overall developed, of which one, four, and one were of high, moderate, and low quality, respectively. Conclusions: The current guidelines provide guidance to support individualized management of patients experiencing non-traumatic bone fracture to benefit from secondary prevention of (re)fracture. Although our recommendations are based on the best available evidence, questionable quality evidence is still available for some relevant clinical questions, so future research has the potential to reduce uncertainty about the effects of intervention and the reasons for doing so at a reasonable cost.

Medication holidays in osteoporosis: evidence-based recommendations from the Italian guidelines on 'Diagnosis, risk stratification, and continuity of care of fragility fractures' based on a systematic literature review.

Background: Noncommunicable, chronic diseases need pharmacological interventions for long periods or even throughout life. The temporary or permanent cessation of medication for a specific period, known as a 'medication holiday,' should be planned by healthcare professionals. Objectives: We evaluated the association between continuity (adherence or persistence) of treatment and several outcomes in patients with fragility fractures in the context of the development of the Italian Guidelines. Design: Systematic review. Data Sources and Methods: We systematically searched PubMed, Embase, and the Cochrane Library up to November 2020 for randomized clinical trials (RCTs) and observational studies that analyzed medication holidays in patients with fragility fracture. Three authors independently extracted data and appraised the risk of bias of the included studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Effect sizes were pooled in a meta-analysis using random effects models. Primary outcomes were refracture and quality of life; secondary outcomes were mortality and treatment-related adverse events. Results: Six RCTs and nine observational studies met our inclusion criteria, ranging from very low to moderate quality. The adherence to antiosteoporotic drugs was associated with a lower risk of nonvertebral fracture [relative risk (RR) 0.42, 95% confidence interval (CI) 0.20-0.87; three studies] than nonadherence, whereas no difference was detected in the health-related quality of life. A reduction in refracture risk was observed when continuous treatment was compared to discontinuous therapy (RR 0.49, 95% CI 0.25-0.98; three studies). A lower mortality rate was detected for the adherence and persistence measures, while no significant differences were noted in gastrointestinal side effects in individuals undergoing continuous versus discontinuous treatment. Conclusion: Our findings suggest that clinicians should promote adherence and persistence to antiosteoporotic treatment in patients with fragility fractures unless serious adverse effects occur.

Cardiovascular Outcomes and Mortality Associated With Discontinuing Statins in 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.

Better adherence with out-of-hospital healthcare improved long-term prognosis of acute coronary syndromes: Evidence from an Italian real-world investigation.

BACKGROUND: Patients who experience a hospital admission for acute coronary syndromes (ACS) exhibit poor prognosis over the years. The purposes of this study were to evaluate the real-world patterns of out-of-hospital practice in the management of ACS patients and to assess their impact on the risk of selected outcomes. METHODS: The cohort of 87,530 residents in the Lombardy Region (Italy) who were newly hospitalised for ACS during 2011-2015 was followed until 2018. Exposure to medical treatment including use of selected drugs, diagnostic procedures and laboratory tests was recorded. The main outcome of interest was re-hospitalisation for cardiovascular (CV) outcomes. Proportional hazards models were fitted to estimate hazard ratio, and 95% confidence intervals (CI), for the exposure-outcome association. Analyses were stratified according to the ACS type. RESULTS: The cumulative incidence of re-hospitalisation for CV disease was 33%, 42% and 38% at 5 years after index discharge among STEMI, NSTEMI and unstable angina patients. Within one year from index discharge, between 70% and 80% of patients had at least a prescription of statins, beta-blockers and renin-angiotensin-system blocking agents, underwent ECG and lipid profile examination, and had a cardiologic examination. One patient in five underwent cardiac rehabilitation. Compared with patients who did not adhere to healthcare recommendations, the risk of CV hospital readmission was reduced from 10% (95% CI: 4%-10%) to 23% (12%-32%) among patients who underwent lipid profile examinations and who experienced cardiac rehabilitation. CONCLUSION: Close out-of-hospital healthcare must be considered the cornerstone for improving the long-term prognosis of ACS patients.

[Acute coronary syndrome: real-world data from the Lombardy Region]. / Sindrome coronarica acuta: dati dal mondo reale in Lombardia.

BACKGROUND: The short-term outcomes of acute coronary syndrome (ACS) have been extensively studied; however, the role of post-discharge monitoring, treatment and rehabilitation in the prevention of long-term outcomes remains debated. The aim of this study was to measure the adherence to a therapeutic pathway and to assess its impact on the log-term risk of hospitalization for cardiovascular (CV) causes. METHODS: A total of 106 104 incident cases of ACS, in which patients aged 40-90 survived hospitalization, were recorded in the administrative databases between 2009-2015 and were identified as index shelters. Each patient had accumulated person-years from the index hospitalization discharge to the first of the following events: hospitalization for CV events or censorship (death, emigration, June 30, 2018). The association between exposure (drug therapy and rehabilitation) and risk of CV hospitalization was assessed using a Cox model in accordance to the intention-to-treat principle. RESULTS: Compared to untreated patients, those who received prescriptions of beta-blockers, statins, antiplatelet agents or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in the year after the index discharge experienced a risk reduction of 13% (95% confidence interval [CI] 11-15%), 10% (95% CI 8-12%), 5% (95% CI 2-6%), and 3% (95% CI 1-6%), respectively, whereas rehabilitation within 2 months reduced the risk by 29% (95% CI 26-32%). CONCLUSIONS: Patients undergoing close monitoring with strict adherence to the recommended treatment after admission have a reduced risk of experiencing long-term CV events.