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.

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.

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.

Beyond antibodies: ankyrins and DARPins. From basic research to drug approval.

This Pharmacological Perspective describes the pathway that, starting from the deep understanding of ankyrins - a family of proteins with high variability-binding and high specificity-binding characteristics - led to the development of a new class of recombinant-binding proteins, the DARPins (designed ankyrin repeat proteins). These are envisaged as alternatives to mAbs and related biologics, with the potential to overcome certain shortcomings of mAbs. DARPins have relatively low molecular weights (14-21kDas) and more favorable PK profiles than mAbs, are stable proteins that can be easily produced in Escherichia coli and can be used in their monovalent form or conjugated to other moieties, for example, polyethylene glycol (PEG) to enhance their half-life. DARPins can also be engineered to produce bi-specific or tri-specific compounds that bind different epitopes of the same target or two different targets. Abicipar, a first-in-class anti-VEGF-A DARPin had similar efficacy compared to anti-VEGF biologics (bevacizumab, ranibizumab) in preclinical studies and was not inferior to ranibizumab in the treatment of age-related macular degeneration (AMD) with a reduced number of intravitreal injections. Abicipar has recently been submitted for regulatory approval for use in AMD.

Improvement in the management of chronic obstructive pulmonary disease following a clinical educational program: results from a prospective cohort study in the Sicilian general practice setting.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disorder of the lungs associated with progressive disability. Although general practitioners (GPs) should play an important role in the COPD management, critical issues have been documented in the primary care setting. The aim of this study was to evaluate the effectiveness of an educational program for the improvement of the COPD management in a Sicilian general practice setting. The effectiveness of the program, was evaluated by comparing 15 quality-of-care indicators developed from data extracted by 33 GPs, at baseline vs. 12 and 24 months, and compared with data from a national primary care database (HSD). Moreover, data on COPD-related and all-cause hospitalizations over time of COPD patients, was measured. Overall, 1,465 patients (3.2%) had a registered diagnosis of COPD at baseline vs. 1,395 (3.0%) and 1,388 (3.0%) over time (vs. 3.0% in HSD). COPD patients with one spirometry registered increased from 59.7% at baseline to 73.0% after 2 years (vs. 64.8% in HSD). Instead, some quality of care indicators where not modified such as proportion of COPD patients treated with ICS in monotherapy that was almost stable during the study period: 9.6% (baseline) vs. 9.9% (after 2 years), vs. 7.7% in HSD. COPD-related and all-cause hospitalizations of patients affected by COPD decreased during the two observation years (from 6.9% vs. 4.0%; from 23.0% vs. 18.9%, respectively). Our study showed that educational program involving specialists, clinical pharmacologists and GPs based on training events and clinical audit may contribute to partly improve both diagnostic and therapeutic management of COPD in primary care setting, despite this effect may vary across GPs and indicators of COPD quality of care.

How did the Introduction of Biosimilar Filgrastim Influence the Prescribing Pattern of Granulocyte Colony-Stimulating Factors? Results from a Multicentre, Population-Based Study, from Five Italian Centres in the Years 2009-2014.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs) are biological products for which the main indication of use is chemotherapy-induced neutropenia. Biosimilars of G-CSFs have been available in Europe since 2007. OBJECTIVE: The objective of this study was to investigate the prescribing pattern of G-CSFs in five Italian centres using different healthcare policy interventions to promote the use of biosimilars in routine care. METHODS: This retrospective, population-based drug utilization study was conducted during the years 2009-2014 using the administrative databases of the Caserta, Treviso and Palermo Local Health Units (LHUs) and the Tuscany and Umbria regions. G-CSF users were characterized and the prevalence of use, proportion of biosimilar users and switching pattern of different G-CSFs were evaluated over time and across centres. RESULTS: Overall, 30,247 patients were treated with G-CSFs in the years 2009-2014, of which 29,083 (96.2 %) were naïve users. The overall prevalence of G-CSF use increased from 0.8 per 1000 inhabitants in 2009 to 1.1 per 1000 in 2014. An increase in the proportion of the use of the biosimilar filgrastim by the total G-CSF users was observed in all centres: from 0.2 % (2009) to 66.2 % (2014). However, heterogeneity across different centres was reported, with the largest increase in Treviso LHU (from 0 to 89.1 % from 2009 to 2014). During the first year of treatment, switching between different G-CSFs was frequent (20.3 %). CONCLUSIONS: Heterogeneity in the use of G-CSF and, in particular, biosimilar filgrastim across different Italian centres was observed, probably due to different regional healthcare policy interventions. During the first year of treatment, switching between different G-CSFs was frequent. Considering the impact of biological drugs on pharmaceutical expenses, it is necessary to harmonize healthcare policies promoting the use of biological drugs with the lowest cost.

Comparative Effectiveness of Biosimilar, Reference Product and Other Erythropoiesis-Stimulating Agents (ESAs) Still Covered by Patent in Chronic Kidney Disease and Cancer Patients: An Italian Population-Based Study.

BACKGROUND: Since 2007 biosimilars of erythropoiesis-stimulating agents (ESAs) are available on the Italian market. Very limited post-marketing data exist on the comparative effectiveness of biosimilar and originator ESAs. AIM: This population-based study was aimed to compare the effects of biosimilars, reference product and other ESAs still covered by patent on hemoglobinemia in chronic kidney disease (CKD) and cancer patients in a Local Health Unit (LHU) from Northern Italy. METHODS: A retrospective cohort study was conducted during the years 2009-2014 using data from Treviso LHU administrative database. Incident ESA users (no ESA dispensing within 6 months prior to treatment start, i.e. index date (ID)) with at least one hemoglobin measurement within one month prior to ID (baseline Hb value) and another measurement between 2nd and 3rd month after ID (follow-up Hb value) were identified. The strength of the consumption (as total number of defined daily dose (DDD) dispensed during the follow-up divided by days of follow-up) and the difference between follow-up and baseline Hb values [delta Hb (ΔHb)] were evaluated. Based on Hb changes, ESA users were classified as non-responders (ΔHb≤0 g/dl), responders (0<ΔHb≤2 g/dl), and highly responders (ΔHb>2 g/dl). A multivariate ordinal logistic regression model to identify predictors for responsiveness to treatment was performed. All analyses were stratified by indication for use and type of dispensed ESA at ID. RESULTS: Overall, 1,003 incident ESA users (reference product: 252, 25.1%; other ESAs covered by patent: 303, 30.2%; biosimilars: 448, 44.7%) with CKD or cancer were eligible for the study. No statistically significant difference in the amount of dose dispensed during the follow-up among biosimilars, reference product and other ESAs covered by patent was found in both CKD and cancer. After three months from treatment start, all ESAs increased Hb values on average by 2g/dl. No differences in ΔHb as well as in frequency of non-responders, responders and highly responders among different types of ESAs were observed in both indications of use. Overall, around 15-20% of ESA users were non-responders. Strength of treatment, but no type of dispensed ESAs was found to be predictor of responsiveness to treatment. CONCLUSIONS: No difference on the effects on hemoglobinemia among users of either biosimilars or reference product or ESAs covered by patent was observed in a general population from Northern Italy, despite a comparable dispensed dose of the different ESAs during the first three months of treatment.

The Management of Diabetes Mellitus in Patients with Chronic Kidney Disease: A Population-Based Study in Southern Italy.

BACKGROUND AND OBJECTIVES: Diabetes mellitus in patients with chronic kidney disease (CKD) is known as diabetic kidney disease (DKD). Pharmacological management of DKD is challenging due to reduced renal excretion of some antidiabetic drugs. The aim of this population-based study was to explore antidiabetic drug use in DKD patients from Southern Italy. METHODS: The Arianna database from Caserta Local Health Unit was used. Diabetic patients with incident CKD [first diagnosis date: index date (ID)] were identified by searching for specific ICD9-CM codes among hospital discharge diagnoses/procedures and/or indication of use associated with drug prescriptions. To evaluate any change in the use of antidiabetic drugs after the CKD diagnosis, the prevalence of antidiabetic drug use among DKD patients was calculated within 1 year prior to/after ID and after dialysis entry. A Kaplan-Meier analysis was used to assess the time to discontinuation of antidiabetic drugs after CKD diagnosis. The frequency of antidiabetic drugs contraindicated in renal disease in DKD patients was measured. RESULTS: Overall, 725 diabetic patients (mean age 72.8 ± 11.4 years) had incident CKD from 2006 to 2011. The use of combination antidiabetic drugs, biguanides and sulphonamides decreased by approximately 10, 7 and 5%, respectively, after the ID. The use of insulins increased by 10% after the ID and by 20% after entry into dialysis. The use of antidiabetic drugs not contraindicated in CKD decreased marginally after the diagnosis of CKD. CONCLUSION: In a general practice of Southern Italy the management of diabetes mellitus changed only marginally in newly diagnosed CKD patients, suggesting a therapeutic inertia on the part of prescribers.

Effects of a computerized decision support system in improving pharmacological management in high-risk cardiovascular patients: A cluster-randomized open-label controlled trial.

UNLABELLED: This study was aimed to investigate the effects of computerized decision support system in improving the prescription of drugs for cardiovascular prevention. A total of 197 Italian general practitioners were randomly allocated to receive either the alerting computerized decision support system integrated into standard software (intervention arm) or the standard software alone (control arm). Data on 21230 patients with diabetes, 3956 with acute myocardial infarction, and 2158 with stroke were analysed. The proportion of patients prescribed with cardiovascular drugs and days of drug-drug interaction exposure were evaluated. Computerized decision support system significantly increased the proportion of patients with diabetes prescribed with antiplatelet drugs (intervention: +2.7% vs. CONTROL: +0.15%; p < 0.001) or lipidlowering drugs (+4.2% vs. +2.8%; p = 0.001). A statistically significant decrease in days of potential interactions has been observed only among patients with stroke (-1.2 vs. -0.5 days/person-year; p = 0.001). In conclusion, computerized decision support system significantly increased the use of recommended cardiovascular drugs in diabetic patients, but it did not influence the exposure to potential interactions.

How Much Are Biosimilars Used in Clinical Practice? A Retrospective Italian Population-Based Study of Erythropoiesis-Stimulating Agents in the Years 2009-2013.

PURPOSE: To explore the prescription patterns of erythropoiesis-stimulating agents (ESAs) in four large Italian geographic areas, where different health policy interventions to promote biosimilar use in routine care are undertaken. METHODS: A retrospective drug utilization study was conducted during the years 2009-2013. The data sources were the administrative databases of the Tuscany region and of the Caserta, Palermo, and Treviso Local Health Units (LHUs). The characteristics, prevalence, and switching patterns of different ESAs (biosimilars and reference products), stratified by indication for use, were calculated over time and across centers. RESULTS: Overall, 49,491 patients were treated with ESAs during the years 2009-2013 in the four centers. Of these, 41,286 patients (83.4 %) were naive users. The prevalence of ESA use increased from 2.9 to 3.4 per 1000 inhabitants in the years 2009-2011 but decreased thereafter (3.0 per 1000 in 2013). Moreover, the proportion of biosimilar users increased overall from 1.8 % in 2010 to 33.6 % in 2013, with larger increase in Treviso (from 0.0 to 45.0 %) and Tuscany (from 0.7 to 37.6 %) than in Caserta (from 7.5 to 22.9 %) and Palermo (from 0.0 to 27.7 %). Switching between different ESAs during the first year of therapy was frequent (17.0 %), much more toward reference products than toward biosimilars. CONCLUSION: Overall, the prevalence of ESA use decreased slightly, while use of biosimilar ESAs, especially in naive patients, increased significantly but to different extents in these four large Italian geographic areas. Switching between different ESAs during the first year of treatment was very frequent, which may affect pharmacovigilance monitoring. New strategies are necessary to further improve market penetration of low-cost medicines, such as biosimilars, and also to harmonize effective health policy interventions that aim to reduce pharmaceutical expenses and optimize patient benefit across all regions.

Appropriateness of clinical and organizational criteria for intra-articular injection therapies in osteoarthritis. A Delphi method consensus initiative among experts in Italy.

OBJECTIVE: The aim of the study was to identify the main aspects involved in patient selection, the choice of therapeutic agents and the safety profile, as well as the medico-legal and organizational aspects of intra-articular injection therapies for osteoarthritis. METHODS: A committee of 10 experts from Italian universities, public hospitals, territorial services, research institutes and patient associations was set up. Fifty-two clinicians from a large number of Italian medical centers specialized in intra-articular injection therapy took part in a Delphi process aimed at obtaining consensus statements among the participants. RESULTS: Large consensus was obtained for statements grouped under the following main themes: treatment indications; drug/medical device choice; treatment efficacy; and appropriate setting. CONCLUSIONS: The consensus statements developed by a large number of experts may be used as a practical reference tool to help physicians treat osteoarthritis patients by means of intra-articular injection therapies.

The advent of biosimilars for the treatment of diabetes: current status and future directions.

Biosimilar insulins are likely to enter the market of diabetes therapies as patents for major branded insulin products start to expire in the next few years (on June 2014, the European Medicines Agency authorized the first biosimilar of insulin glargine, Abasria, 100 Units/ml, for the treatment of diabetes mellitus). This would allow providing comparable clinical benefits of the current available insulins at a significantly lower cost, thus increasing the affordability and access of insulin treatment for patients with diabetes. Biosimilars are approved via a stringent regulatory pathway demonstrating quality, safety, and efficacy comparable to the reference product. However, the production complexities of such products raise important considerations for treatment efficacy and patient safety, including naming and product tracking, substitution practices, and pharmacovigilance. Additionally, as practitioners' knowledge regarding the differences about pharmacological, clinical, and regulatory aspects between biosimilars and generic small molecules is often suboptimal, specific education on biosimilar prescribing, dispensing, and administering is critical for ensuring patients' benefit and safety. This article discusses all the issues concerning biosimilar, especially biosimilar insulins.

Trends in the prescription of antidiabetic medications from 2009 to 2012 in a general practice of Southern Italy: a population-based study.

OBJECTIVE: To assess the prescribing pattern of antidiabetic drugs (AD) in a general practice of Southern Italy from 2009 to 2012, with focus on behaviour prescribing changes. METHODS: This retrospective, drug utilization study was conducted using administrative databases of the Local Health Unit of Caserta (Southern Italy) including about 1 million citizens. The standardized prevalence of AD use was calculated within each study year. A sample cohort of 78,789 subjects with at least one prescription of AD was identified during the study period. RESULTS: There was an overall increase of the proportion of the patients treated with monotherapy, which was significant for insulin monotherapy (from 11.2 to 14.6%, p<0.001). The proportion of patients treated with metformin remained stable (from 68.3% to 67.8%, p=0.076), while those receiving sulfonylurea dropped from 18.4% to 12.5% (p<0.001); GLP-1 analogues and DPP-4 inhibitors showed the greatest increase (from 1.2% to 6.6%, p<0.001). In the whole sample of 25,148 new AD users, metformin was the most commonly prescribed drug in monotherapy (41.9%), while insulin ranked second (13.3%). CONCLUSION: This study shows a rising trend of AD monotherapy, with sulfonylureas and incretins showing the more negative and positive trend, respectively.

Safety profile of biological medicines as compared with non-biologicals: an analysis of the italian spontaneous reporting system database.

BACKGROUND: Biologicals are important treatment options for various chronic diseases. After the introduction of the first biosimilars, animated debate arose in the scientific community about the actual benefit-risk profile of these drugs. In this context, a comparative safety evaluation of biologicals and biosimilars in clinical practice is warranted. METHODS: We identified all suspected adverse drug reactions (ADRs) concerning biological/biosimilars (excluding vaccines, toxins, blood derivatives, and radio-pharmaceuticals), and further classified them into mechanistic classes. We described the frequency of biological/biosimilar class- and compound-specific ADRs by system organ class (SOC) and type of reporter. We also separately explored the traceability of biologicals and biosimilar-related ADR reports. RESULTS: Overall 171,201 ADR reports were collected during the observation period; 9,601 (5.6 %) of these concerned biologicals. Biological-related reports were mainly issued by hospital-based physicians (78.7 %). Most of these reports involved monoclonal antibodies and fusion proteins (66.3 %). Reported ADRs were mainly 'skin and subcutaneous tissue disorders' (21 %), 'general and administration site disorders' (17 %), and 'gastrointestinal disorders' (13.6 %). In terms of traceability, 94.8 % of biological-related reports included an identifiable product name, whilst only 8.6 % indicated the corresponding batch number. Regarding biosimilars, 298 reports were identified, with a low proportion indicating drug ineffectiveness (10.1 %). CONCLUSIONS: Most ADRs attributed to biologicals are 'skin and subcutaneous tissue disorders'. Anticancer monoclonal antibodies are most frequently associated with ADRs. A low proportion of ADR reports concern biosimilars.

Expert opinion of nephrologists about the effectiveness of low-protein diet in different stages of chronic kidney disease (CKD).

No clinical trials have specifically explored the benefits of low-protein diet in patients with different stages of chronic kidney disease (CKD) 3B. In the absence of RCTs, expert opinion may be a valid surrogate to estimate treatment effectiveness. A questionnaire-based survey of a large sample of nephrologists from Southern Italy was conducted to explore benefits of low-protein diet (LPD) in delaying dialysis entry in different CKD stages. For the case vignettes describing eight different patient profiles with various CKD stages, nephrologists reported expected benefits as time delay of dialysis entry. Information was collected through questionnaires filled by 88 nephrologists from different Southern Italian hospitals. On average, nephrologists estimated the highest delay in starting dialysis due to LPD in stages 3B (15 months) and 3A (14 months), and the lowest for 5 stage (3 months). According to opinion of a large sample of Southern Italian nephrologists, low-protein diet may be more efficacious if started in CKD stage 3B than 4 and 5.

Pattern of statin use in southern italian primary care: can prescription databases be used for monitoring long-term adherence to the treatment?

OBJECTIVES: We sought to evaluate the prescribing pattern of statins according to national and regional health policy interventions and to assess specifically the adherence to the therapy in outpatient setting in Southern Italy. METHODS: A population-based study was performed on persons ≥15 years old, living in the catchment area of Caserta (Southern Italy), and registered in Arianna database between 2004 and 2010. Prevalence and incidence of new treatments with statins were calculated for each year and stratified by drug. Adherence to therapy was measured by Medication Possession Ratio. Sub-analyses by individual compound and type of cardiovascular prevention were performed. RESULTS: From 2004 to 2010, the one-year prevalence of statin use increased from 44.9/1,000 inhabitants to 79.8/1,000, respectively, consistently with the incidence of new use from 16.2/1,000 to 19.5/1,000, except a slight decrease after criteria reimbursement revision on 2005 (13.3/1,000). The incidence of new treatments decreased for atorvastatin, and increased for simvastatin over the study years. Overall, 43% of new users were still highly adherent to the treatment (MPR≥80%) after six months, while 26% after 4-years of follow-up. As compared with highly adherent patients, the probability to be non-adherent (MPR≤25%) at 4-years of follow-up was 26% higher for women than for men (full adj. odds ratio: 1.26; 95% CI: 1.10-1.45), and 64% higher in patients who started on primary rather than on secondary prevention (1.64; 1.29-2.07). CONCLUSIONS: Prevalence and incidence of statin use increased consistently with health policy interventions. Only one-fourth of patients who newly initiated a statin were adherent to the treatment after 4-year of follow-up. Since the benefits of statins in terms of cardiovascular outcome and costs are associated with their chronic use, the identification of patient-related predictors of non-adherence such as gender, primary prevention could be suitable for physicians to improve the patients' compliance.

User-only design to assess drug effectiveness in clinical practice: application to bisphosphonates and secondary prevention of fractures.

PURPOSE: Different strategies applicable to control for confounding by indication in observational studies were compared in a large population-based study regarding the effect of bisphosphonates (BPs) for secondary prevention of fractures. METHODS: The cohort was drawn from healthcare utilization databases of 13 Italian territorial units. Patients aged 55 years or more who were hospitalized for fracture during 2003-2005 entered into the cohort. A nested case-control design was used to compare BPs use in cohort members who did (cases) and who did not experience (controls) a new fracture until 2007 (outcome). Three designs were employed: conventional-matching (D1 ), propensity score-matching (D2 ), and user-only (D3 ) designs. They differed for (i) cohort composition, restricted to patients who received BPs straight after cohort entry (D3 ); (ii) using propensity score for case-control matching (D2 ); and (iii) compared groups of BPs users versus no users (D1 and D2 ) and long-term versus short-term users (D3 ). RESULTS: Bisphosphonate users had odds ratios (95% confidence interval) of 1.20 (1.01 to 1.44) and 0.95 (0.74 to 1.24) by applying D1 and D2 designs, respectively. Statistical evidence that long-term BPs use protects the outcome onset with respect to short-term use was observed for user-only design (D3 ) being the corresponding odds ratio (95% confidence interval) 0.64 (0.44 to 0.93). CONCLUSIONS: User-only design yielded closer results to those seen in RCTs. This approach is one possible strategy to account for confounding by indication.