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The aim of the present study is to describe pharmacological characteristics of drug-related allergies and anaphylaxis leading to the emergency department (ED). An 8-year post hoc analysis on the MEREAFaPS Study database was performed (2012−2019). Subjects who experienced drug-related hypersensitivity leading to an ED visit were selected. Logistic regression analyses were used to estimate the reporting odds ratios (RORs) of drug-related allergies and anaphylaxis adjusting for sex, age classes, and ethnicity. In addition, a systematic review of observational studies evaluating drug-related hypersensitivity reactions leading to ED visits in outpatients was performed. Out of 94,073 ED visits, 14.4% cases were drug-related allergies and 0.6% were anaphylaxis. Females accounted for 56%. Multivariate logistic regression showed a higher risk of drug-related allergy among males and all age classes < 65 years, while a higher risk of anaphylaxis was observed for females (ROR 1.20 [1.01−1.42]) and adults (ROR 2.63 [2.21−3.14]). The systematic review included 37 studies. ED visits related to allergy and anaphylaxis ranged from 0.004% to 88%, and drug-related allergies and anaphylaxis ranged from 0.007% to 88%. Both in our analysis and in primary studies, antibacterials, analgesics, and radiocontrast agents were identified as the most common triggers of hypersensitivity.

Background: Vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitors (TKIs) are widely used in cancer treatment and burdened by cardiovascular toxicity. The majority of data come from clinical trials, thus in selected populations. The aim of our study is to evaluate the cardiotoxicity profile of VEGFR-targeted TKIs and the impact of cardiovascular risk factors in a real-life population., Patients and Methods: In this cohort, population-based study, patients treated with VEGFR-targeted TKIs, bevacizumab and trastuzumab between 2009 and 2014 were analyzed. A multi-source strategy for data retrieval through hospital, pharmaceutical and administrative databases of the Lombardy region, Italy, has been adopted. The primary endpoint was to determine the incidence and type of major adverse cardiovascular events (MACEs) along with their temporal trend. The secondary endpoint was to define the impact of cardiovascular risk factors in the occurrence of MACEs., Results: A total of 829 patients were treated with VEGFR-targeted TKIs. Eighty-one MACEs occurred in the first year of follow-up [crude cumulative incidence (CCI): 9.79%] mainly consisting of arterial thrombotic events (ATEs, 31 events, CCI: 3.99%), followed by rhythm disorders (22 events, CCI: 2.66%), pulmonary embolisms and heart failures (13 events each, CCI: 1.57%). While the incidence of most MACEs showed a plateau after 6 months, ATEs kept increasing along the year of follow-up. Hypertension and dyslipidemia were associated with an increase in risk of ATEs [relative risk difference (RRD) +209.8% and +156.2%, respectively], while the presence of previous MACEs correlated with a higher risk of all MACEs in multivariate analysis (RRD 151.1%, 95% confidence interval 53.6% to 310.3%, P < 0.001)., Conclusions: MACEs occur in a clinically significant proportion of patients treated with VEGFR-targeted TKIs, with ATEs being predominant, mainly associated with hypertension and dyslipidemia. A clinical algorithm for effective proactive management of these patients is warranted., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This post hoc analysis of an Italian active pharmacovigilance study describes pharmacological differences of ADEs leading to emergency department (ED) visits and hospitalization in women and men. During the study period (January 2007-December 2018), 61,855 reports of ADEs leading to ED visits were collected. Overall, 30.6% of ADEs resulted in hospitalization (30% in women and 31% in men). Multivariate logistic regression showed that, among women, drug classes significantly associated with an increased risk of hospitalization were heparins (ROR 1.41, CI 1.13-176), antidepressants (ROR 1.12, CI 1.03-1.23) and antidiabetics (ROR 1.13, CI 1.02-1.24). Among men, only vitamin K antagonists (ROR 1.28, CI 1.09-1.50), opioids (ROR 1.30, CI 1.06-1.60) and digitalis glycosides (ROR 1.32, CI 1.09-1.59) were associated with a higher risk of hospitalization. Overall, older age, multiple suspected drugs and the presence of comorbidities were significantly associated with a higher risk of hospitalization. A significantly reduced risk of hospitalization was observed in both women and men experiencing an adverse event following immunization (ROR 0.36, CI 0.27-0.48 and 0.83, 0.42-0.74, respectively) compared to drugs. Results obtained from this real-world analysis highlight important aspects of drug safety between sexes.

Fatal Adverse Events (FADEs) are a major public health problem, and some FADEs could be preventable. The aim of the present study is to describe the frequency, the drugs involved and the preventability in the FADEs collected through the MEREAFaPS Study between 2012 and 2018. All cases including the outcome "death" have been examined. We excluded cases with vaccine-related ADEs, overdose or suicide, and ADEs occurred during the hospitalisation. Two trained assessors evaluated all cases fulfilling the inclusion criteria. ADEs' preventability was evaluated applying the Schumock and Thornton algorithm. During the study period, we observed 429 cases of death, 92 of which were excluded. The remaining 337 cases involved 187 women and 150 men, with a mean age of 79 and of 77 years, respectively. For each report, the suspected drugs and concomitant ones were 1.26 and 4.20, respectively. Anticoagulants and antiplatelet agents account for more than 40% of FADE cases and the most frequent reactions are haemorrhages (37.5%). The 25% of the FADEs were preventable. This study confirms that FADEs are still a relevant clinical occurrence, and are often caused by widely used old drugs associated with adverse events. The death of one in four patients was preventable. Further efforts should be done to improve the appropriateness of the therapy, especially in older patients who are treated with anticoagulants.

Background: There is a significant gap in knowledge addressing cardiovascular (CV) medications safety in elderly. In this context, our purposes were to define clinical and pharmacological characteristics of outpatients' adverse drug events (ADEs) related to CV medications leading to emergency department (ED) visits in the elderly Italian patients according to different age groups, and to evaluate the risk of hospitalization associated to ADEs in this population. Methods: A multicentre, retrospective study was performed on reports of suspected ADEs collected between 2007-2018 in 94 EDs involved in the MEREAFaPS Study. Elderly patients who experienced one or more CV medications-related ADEs leading to ED visit were selected. Patients' characteristics, suspected (ATC classes B and C) and concomitant drugs, and ADE description were collected. Elderly patients were stratified into three age groups (65-74, 75-84, and ≥85 years) and compared to adults (18-64 years). Logistic regression analyses were used to estimate the reporting odds ratios (RORs) with 95% confidence intervals (CIs) of ADE-related hospitalization adjusting for sex, presence of two or more suspected drugs, concomitant drugs, and one or more comorbidities. Results: Among elderly, 16,926 reports of suspected ADE related to CV medications were collected, and 6,694 (39.5%) resulted in hospitalization. Patients were mostly female, Caucasians, and middle-old (75-84). 78.9% of patients were treated with only one suspected drug, and 71.9% and 47.1% reported concomitant medications and comorbidities, respectively. Compared to adults, risk of hospitalization was significantly higher for middle-old and oldest-old patients exposed to vitamin K antagonists (1.29 [1.09-1.52] and 1.56 [1.30-187]), direct thrombin inhibitors (3.41 [1.44-8.08] and 4.12 [1.67-10.17]), antiplatelets (1.51 [1.26-1.81] and 2.09 [1.71-2.57]), and beta-blockers (1.89 [1.38-2.59 and 2.31 [1.60-3.35]). Overall, a higher risk of hospitalization was observed for renin-angiotensin system inhibitors (1.32 [1.04-1.68], 1.65 [1.32-2.06], and 2.20 [1.70-2.85]), presence of two or more concomitant drugs, and concomitant conditions. Conclusion: Our real-world findings underline relevant safety aspects of CV medications in the elderly Italian population. ED clinicians must always consider the higher risk of hospitalization related to the use of CV drugs in elderly, particularly in oldest-old ones, for antiarrhythmics, beta-blocking agents, renin-angiotensin system inhibitors, antiplatelets, and anticoagulants., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Crescioli, Bettiol, Bonaiuti, Tuccori, Rossi, Capuano, Pagani, Spada, Venegoni, Vighi, Mannaioni, Vannacci and Lombardi.)

Benzodiazepines (BZD) and z-drugs (ZD) are a widely prescribed group of medicines. They are often used inappropriately, and this is associated with adverse events (AEs), which may cause emergency department (ED) visits. The present study aimed to describe the characteristics of BZD and ZD related AEs leading to emergency department (ED) visit and hospitalisation in Italy, considering their plasma half-life. Ninety-two Italian EDs were monitored between 2007 and 2018. Rates of ED visit and hospitalisation were calculated. Multivariate logistic regression was used to estimate the reporting odds ratios (RORs) of hospitalisation. Univariate linear regression was performed to evaluate the ROR of hospitalisation according the plasma half-life of the suspected agents. A total of 3203 AE reports were collected. Overall, multivariate logistic regression showed that the risk of hospitalisation was higher for prazepam (3.26 [1.31-8.11]), flurazepam (1.62 [1.15-2.27]), and lorazepam (1.36 [1.15-1.61]). In the elderly, this risk was higher for prazepam (3.98 [1.03-15.3]), and lorazepam (1.58 [1.19-2.11]). Parenteral and rectal formulations were associated with a lower risk of hospitalisation compared to oral formulations. Our findings underlined the dangers in the use of BZD and ZD in Italy, particularly in women and older adults. ED clinicians must always take into account that the higher risk in terms of hospitalisation related to the use of BZD and ZD can be observed in patients treated with oral formulations, in those exposed to more than one sedative-hypnotics, and in patients exposed to compounds with intermediate or long plasma half-life.

Background: Adverse drug event (ADEs) are a significant cause of emergency department (ED) visits and consequent hospitalization. Preventing ADEs and their related ED visits in outpatients remains a public health safety challenge. In this context, the aims of the present study were to describe the frequency, seriousness and preventability of outpatients' ADE-related ED visits and hospitalizations in the Italian general population, and to identify the presence of potential predictors of ADE-related hospitalization., Methods: We performed a nationwide, multicentre, observational, retrospective study based on reports of suspected ADEs collected between January 1, 2007 and December 31, 2018 in 94 EDs involved in the MEREAFaPS project. Patients' demographic characteristics, their clinical status, suspected and concomitant drugs, ADE description, and its degree of seriousness, were collected. Causality and preventability were assessed using validated algorithms, and logistic regression analyses were used to estimate the reporting odds ratios (RORs) with 95% confidence intervals (CIs) of ADE-related hospitalization, considering the following covariates: age, sex, ethnicity, number of implicated medications, parenteral administration, presence of interaction, therapeutic error, and/or complementary and alternative medicines (CAM)., Results: Within 12 years, 61,855 reports of suspected ADE were collected, of which 18,918 (30.6%) resulted in hospitalization (ADE defined as serious). Patients were mostly female (56.6%) and Caucasians (87.7%), with a mean age of 57.5 ± 25.0 years. 58% of patients were treated with more than two drugs, and 47% of ADEs leading to hospitalization were preventable. Anticoagulants, antibiotics, and nonsteroidal anti-inflammatory drugs (NSAIDs) were the most frequently implicated agents for ED visits and/or hospitalization, which included clinically significant ADEs, such as haemorrhage for anticoagulants, moderate to severe allergic reactions for antibiotics, and dermatologic reactions and gastrointestinal disturbances for NSAIDs. Older age (1.54 [1.48-1.60]), higher number of concomitantly taken drugs (2.22 [2.14-2.31]), the presence of drug-drug interactions (1.52 [1.28-1.81]), and therapeutic error (1.54 [1.34-1.78]), were significantly associated with an increased risk of hospitalization., Conclusion: Our long-term active pharmacovigilance study in ED provided a valid estimation of ADE-related hospitalization in a representative sample of the Italian general population and can suggest further focus on medication safety in outpatients, in order to early recognise and prevent ADEs., (Copyright © 2020 Lombardi, Crescioli, Bettiol, Tuccori, Capuano, Bonaiuti, Mugelli, Venegoni, Vighi, Vannacci and the MEREAFaPS Study group.)

Introduction: Oral anticoagulants, including vitamin K inhibitors (VKAs) and direct anticoagulants (DOACs) are important for preventing and treating thromboembolic diseases. However, they are not recommended for use in all patients due to negative side effects and adverse drug reactions (ADRs). Currently, there is a paucity of information about their use in real life. Therefore, the aim of this pilot study is to report on the rate of serious ADRs in oral anticoagulant users, determine patient characteristics associated with increased risk of ADRs, and identify possible management strategies for reducing risk of ADRs within a hospital setting., Methods: Patients admitted to the Internal Medicine Department of the Vimercate Hospital were recruited between November 1, 2015 and October 31, 2016. All patients reporting an ADR associated with anticoagulant use were selected. Demographic, clinical, and observational data were extracted from electronic hospital records, in particular, by the hospital discharge letters and other clinical records. The main outcome of the study was to evaluate the incidence of anticoagulants serious adverse drug reactions conditioning hospital admission, the percentage of preventable reactions, and the determinants of those., Results and Discussion: Of the 2,064 admissions, 102 (4.9%) eligible patients were identified. Age ranged from 60-95 years (mean = 81.9, standard deviation = 6,59) and 47.1% (n=48) were female. Of the 102 cases, 68 used VKAs and 34 used DOACs. The most common admission diagnosis was heart failure following anemia or hemorrhage (56 cases), followed by acute hemorrhage (with or without anemia; 29 cases), and anemia not associated with evident hemorrhage (17cases). The majority of VKA users (n=65, 95.6%) had a high risk of major bleeding. ADRs were found to be preventable in 96% of VKA users and 68% of DOACs users., Conclusion: This study highlights the large percentage of ADRs from oral anticoagulants that can be avoided with more careful patient management. Periodic check-up of cardiac and renal function, as well as blood count, may be useful for reducing the risk of ADRs, especially in older DOACs users. Further research is needed to get new data to improve the patients monitoring system., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Adverse drug reactions (ADRs) reduce patients' quality of life, increase mortality and morbidity, and have a negative economic impact on healthcare systems. Nevertheless, the importance of ADR reporting is often underestimated. The project "FarmaREL" has been developed to monitor and evaluate ADRs in haematological patients and to increase pharmacovigilance culture among haematology specialists. In 13 haematology units, based in Lombardy, Italy, a dedicated specialist with the task of encouraging ADRs reporting and sensitizing healthcare professionals to pharmacovigilance has been assigned. The ADRs occurring in haematological patients were collected electronically and then analysed with multiple logistic regression. Between January 2009 and December 2011, 887 reports were collected. The number of ADRs was higher in older adults (528; 59%), in male (490; 55%), and in non-Hodgkin lymphoma patients (343; 39%). Most reactions were severe (45% required or prolonged hospitalization), but in most cases, they were fully resolved at the time of reporting. According to Schumock and Thornton criteria, a percentage of ADRs as high as 7% was found to be preventable versus 2% according to reporter opinion. Patients' haematological diagnosis, not age or gender, resulted to be the variable that most influenced ADR, in particular severity and outcome. The employment of personnel specifically dedicated to pharmacovigilance is a successful strategy to improve the number and quality of ADR reports. "FarmaREL", the first programme of active pharmacovigilance in oncohaematologic patients, significantly contributed to reach the WHO "Gold Standard" for pharmacovigilance in Lombardy, Italy., (Copyright © 2017 John Wiley & Sons, Ltd.)

Purpose: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe cutaneous adverse drug reactions. We assessed incidence, drug exposure and mortality, analysing data obtained from the Lombardy Registry of Severe Cutaneous Reactions (REACT)., Methods: Data were collected from hospitals in the Italian Lombardy region (9,502,272 people). A trained monitor was sent to the reporting hospital to collect data on drug exposure and clinical features. The algorithm for drug causality for epidermal necrolysis algorithm was applied to assess drug causality. Defined Daily Dose (DDD) was used to express drug consumption., Results: From April 2009 to November 2014, 17 cases of TEN and 59 cases of SJS were collected. The overall incidence rate was 1.40 cases (95%CI, 1.12-1.76) per million people per year. A total of 15 cases died during hospitalization with a mortality rate of 16.9% for SJS and 29.4% for TEN. Overall, 55.4% of cases had a probable or very probable relation with drug exposure. In a total of five patients (6.6%), no causative drug for the reaction was identifiable. Allopurinol contributed to the highest number of cases (23 cases), while the highest incidence based on more than one case reported was observed for cotrimoxazole and lamotrigine, with 5.37 cases (95%CI, 2.09-13.80) and 3.54 (95%CI, 1.21-10.42) per 10 million DDD/year, respectively., Conclusions: We confirmed that SJS and TEN are rare adverse cutaneous reactions. As expected, mortality was influenced by the degree of skin detachment. The profile of drugs associated with the reactions was in agreement with data from other surveillance systems., (Copyright © 2015 John Wiley & Sons, Ltd.)