Incidence, causative factors and mortality rates of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in northern Italy: data from the REACT registry.

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.

Drug-Related Hypersensitivity Reactions Leading to Emergency Department: Original Data and Systematic Review.

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.

Analysis of fatal adverse drug events recorded in several Italian emergency departments (the MEREAFaPS study).

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.

Risk of Hospitalization for Adverse Drug Events in Women and Men: A Post Hoc Analysis of an Active Pharmacovigilance Study in Italian Emergency Departments.

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.

Italian Emergency Department Visits and Hospitalizations for Outpatients' Adverse Drug Events: 12-Year Active Pharmacovigilance Surveillance (The MEREAFaPS Study).

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.

Risk of hospitalisation associated with benzodiazepines and z-drugs in Italy: a nationwide multicentre study in emergency departments.

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.

Risk of Hospitalization Associated with Cardiovascular Medications in the Elderly Italian Population: A Nationwide Multicenter Study in Emergency Departments.

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.