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Valentina Perrone,1,* Valentino Conti,2,* Mauro Venegoni,2 Stefania Scotto,2 Luca Degli Esposti,3 Diego Sangiorgi,3 Lucia Prestini,4 Sonia Radice,1 Emilio Clementi,5,6 Giuseppe Vighi,2,4 1Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, University Hospital Luigi Sacco, Università di Milano, Milan, Italy; 2Regional Centre for Pharmacovigilance, Lombardy, Milan, Italy; 3CliCon Srl, Health, Economics and Outcomes Research, Ravenna, Italy; 4Unit of Clinical Pharmacology and Pharmacovigilance, Niguarda Ca’Granda Hospital, Milan, Italy; 5Unit of Clinical Pharmacology, CNR Institute of Neuroscience, Department of Biomedical and Clinical Sciences, University Hospital Luigi Sacco, Università di Milano, Milan, Italy; 6Scientific Institute, IRCCS Eugenio Medea, Lecco, Italy *These authors contributed equally to the work Objective: The purpose of this study was to determine the prevalence of adverse drug reactions (ADRs) reported in emergency departments (EDs) and carry out a thorough characterization of these to assess preventability, seriousness that required hospitalization, subsequent 30-day mortality, and economic burden. Methods: This was a retrospective cohort study of data from an active pharmacovigilance project at 32 EDs in the Lombardy region collected between January 1, 2010 and December 31, 2011. Demographic, clinical, and pharmacological data on patients admitted to EDs were collected by trained and qualified monitors, and deterministic record linkage was performed to estimate hospitalizations. Pharmacoeconomic analyses were based on Diagnosis-Related Group reimbursement. Results: 8,862 ADRs collected with an overall prevalence rate of 3.5 per 1,000 visits. Of all ADRs, 42% were probably/definitely preventable and 46.4% were serious, 15% required hospitalization, and 1.5% resulted in death. The System Organ Classes most frequently associated with ADRs were: skin and subcutaneous tissue, gastrointestinal, respiratory thoracic and mediastinal, and nervous system disorders. The most common Anatomical Therapeutic Chemical classes involved in admissions were J (anti-infectives and immunomodulating agents), B (blood and blood-forming organs), and N (nervous system). Older age, yellow and red triage, higher number of concomitantly taken drugs, and previous attendance in ED for the same ADR were significantly associated with an increased risk of hospitalization. The total cost associated with ADR management was €5,184,270, with a mean cost per patient of €585. Fifty-eight percent of the economic burden was defined as probably/definitely preventable. Conclusion: ADRs are a serious health/economic issue in EDs. This assessment provides a thorough estimation of their seriousness, preventability, and burden impact in a large population from a representative European region. Keywords: adverse drug reaction, preventability, economic impact, emergency department, pharmacovigilance

Luca Degli Esposti,1 Diego Sangiorgi,1 Valentina Perrone,2 Sonia Radice,2 Emilio Clementi,3,4 Francesco Perone,4,5 Stefano Buda1 1CliCon Srl Health, Economics and Outcomes Research, Ravenna, Italy; 2Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, L Sacco University Hospital, Università di Milano, Milan, Italy; 3Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, CNR Institute of Neuroscience, L Sacco University Hospital, Università di Milano, Milan, Italy; 4Scientific Institute, IRCCS E Medea, Lecco, Italy; 5Local Health Unit, Caserta, Italy Objectives: Systemic administration of anti-tumor necrosis factor alpha (anti-TNF alpha) leads to an anti-inflammatory and joint protective effect in pathologies such as rheumatoid arthritis, psoriasis, and Crohn's disease. The aim of this study was to assess adherence to therapy, persistence in treatment (no switches or interruptions), and consumption of care resources (drugs, outpatient services, hospitalizations). Methods: We conducted an observational retrospective cohort analysis using the administrative databases of five local health units. Patients filling at least one prescription for anti-TNF alpha between January 1, 2009 and December 31, 2011 were included and followed up for 1 year. Patients were defined as adherent if >80% of the follow-up period was covered by drugs dispensation. Results: A total of 1,219 patients were analyzed (mean age 49.6±14.6, male 47%). Among enrolled patients, 36% were affected by rheumatoid arthritis, and 31% and 10% were affected by psoriasis and Crohn's disease, respectively; other indications remained below these percentages. Thirty-four percent of patients (420) were treated with adalimumab, 51% (615) with etanercept, and 15% (184) with infliximab. Among the 94% of patients who did not switch, those treated with infliximab had a higher rate of adherence across all indications (51% overall) when compared to that observed in patients treated with etanercept (27%) or adalimumab (23%). The mean annual nonpharmacological expenditure for each patient in analysis was €988 for adherent and €1,255 for nonadherent patients. Infliximab was associated with the lowest cost for all indications as determined by the multivariate generalized linear model. Conclusions: Patients treated with infliximab were associated with higher adherence and persistence in treatment and lower costs, as compared to those treated with adalimumab or etanercept. Keywords: anti-TNF alpha, therapy adherence, cost of illness

Valentina Perrone,1 Dario Cattaneo,1 Sonia Radice,1 Diego Sangiorgi,2 Augusto B Federici,3 Maria Rita Gismondo,4 Massimo Medaglia,5 Valeria Micheli,4 Stefania Vimercati,5 Enza Pallone,6 Luca Degli Esposti,2 Emilio Clementi1,71Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences, L Sacco University Hospital, University of Milan, Milan, 2CliCon Srl, Health, Economics and Outcomes Research, Ravenna, 3Hematology and Transfusion Medicine, Department of Clinical Sciences and Community Health, 4Clinical Microbiology Virology and Diagnosis of Bioemergency, 5Pharmaceutical Department, 6Quality Clinical Risk and Accreditation Unit, L Sacco University Hospital, Milan, 7Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco, ItalyBackground: Highly active antiretroviral therapy (HAART) has reduced morbidity and mortality in patients infected with human immunodeficiency virus (HIV). Studies have documented high interindividual variability in the pharmacokinetics of antiretroviral drugs, which may impair the success of HAART if not managed properly. Therapeutic drug monitoring (TDM) is a useful diagnostic tool that helps clinicians to optimize drug doses so that drug concentrations associated with the highest therapeutic efficacy are obtained with a reduced risk of concentration-dependent adverse effects. The aim of this study was to assess whether use of TDM improves clinical outcomes and cost of illness.Methods: A retrospective cohort study was conducted at L Sacco University Hospital in Milan, Italy, in HIV-infected patients aged ≥18 years with at least one prescription of antiretroviral drugs for which TDM was applied. The inclusion period was from January 2010 to December 2011, with a follow-up period of up to 12 months. Laboratory and administrative databases were analyzed and matched with each other.Results: The cohort consisted of 5,347 patients (3,861 males and 1,486 females) of mean age 43.9±12.5 years. We found that TDM had been used in 143 of these patients, among whom adherence with therapy was significantly higher than among those in whom TDM had not been used (94% versus 78%). In TDM-controlled patients, the mean length of HIV-related hospitalization stay and mean cost of hospitalization were significantly reduced with respect to those observed in the group in which TDM had not been used (7.21 days versus 29.47 days and €293 versus €688, respectively).Conclusion: Inclusion of TDM as part of routine clinical optimization of drug dosing in HIV-infected patients is associated with higher adherence to therapy, reduced length of hospitalization stay, and reduced cost of illness.Keywords: human immunodeficiency virus, therapeutic drug monitoring, health care costs