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The incidence of heart failure is primarily flat or declining for a presumably reflecting better management of cardiovascular diseases, but that of heart failure with preserved ejection fraction (HFpEF) is probably increasing for the lack of an established effective treatment. Moreover, there is no specific pharmacological treatment for patients with heart failure with mildly reduced ejection fraction (HFmrEF) since no substantial prospective randomized clinical trial has been performed exclusively in such population. According to the recent 2021 European Society of Cardiology (ESC) guidelines, the triad composed of an Angiotensin Converting Enzyme inhibitor or Angiotensin Receptor-Neprilysin Inhibitor (ARNI), a beta-blocker, and a Mineralcorticoid Receptor Antagonist is the cornerstone therapy for all patients with heart failure with reduced ejection fraction (HFrEF) but a substantial gap exists for patients with HFpEF/HFmrEF. Despite the important role of the Renin-Angiotensin-Aldosterone System (RAAS) in heart failure pathophysiology, RAAS blockers were found ineffective for HFpEF patients. Indeed, even the new drug class of ARNI was found effective only in HFrEF patients. In this regard, a therapeutic alternative may be represented by drug stimulating the non-classic RAAS (ACE2 and A1-7) as well as other emerging drug classes (such as SGLT2 inhibitors). Reflecting on this global health burden and the gap in treatments among heart failure phenotypes, we summarize the leading players of heart failure pathophysiology, the available pharmacological treatments for each heart failure phenotype, and that in future development.
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Insuficiência Cardíaca/tratamento farmacológico , Animais , Doença Crônica , Insuficiência Cardíaca/metabolismo , Hormônios/metabolismo , HumanosRESUMO
Despite Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been associated with a reduced risk of heart failure in patients with type 2 diabetes mellitus (T2DM), the effect observed for other cardiovascular (CV) and cerebrovascular outcomes differed among clinical trials. Different observational studies have investigated the effects of SGLT2 inhibitors on these outcomes and mortality. The present meta-analysis aimed to assess the effects of SGLT2 inhibitors on the risk of CV (major adverse CV event - MACE, non-fatal myocardial infarction, or hospitalization for heart failure) and cerebrovascular (stroke) outcomes. A systematic review was conducted in Pubmed from January 1, 2012 to November 31, 2020. Only retrospective cohort studies including as control group users of dipeptidyl peptidase-4 (DPP-4) inhibitors or non-SGLT2 inhibitors were retained and analysed separately. A random effect meta-analysis approach was used. This study followed the PRISMA statement. Of the 158 references identified, 20 articles were selected for meta-analysis, of which 13 considered the comparison with DPP-4 inhibitors and 7 the comparison with non-SGLT2 inhibitors. The pooled intention-to-treat analysis showed a reduced risk of stroke with SGLT2 inhibitors compared to DPP-4 inhibitors (Hazard ratio HR, 0.89; 95%CI, 0.82-0.96; I2 = 25%; p = 0.25) and non-SGLT2 inhibitors (HR, 0.83; 95%CI, 0.77-0.91; I2 = 11%; p = 0.34). Finally, SGLT2 inhibitors were also associated with a reduced risk of CV outcomes and mortality in all comparisons. Our data support contemporary society recommendations to prioritise the use of SGLT2 inhibitors in patients with T2DM and at high risk for CV complications.
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Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Doenças Cardiovasculares/mortalidade , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Estudos Retrospectivos , Risco , Resultado do TratamentoRESUMO
Atrial fibrillation (AF) is a significant cause of morbidity and mortality as well as a public health burden considering the high costs of AF-related hospitalizations. Pre-clinical and clinical evidence showed a potential role of the renin angiotensin system (RAS) in the etiopathogenesis of AF. Among RAS mediators, angiotensin II (AII) and angiotensin 1-7 (A1-7) have been mostly investigated in AF. Specifically, the stimulation of the pathway mediated by AII or the inhibition of the pathway mediated by A1-7 may participate in inducing and sustaining AF. In this review, we summarize the evidence showing that both RAS pathways may balance the onset of AF through different biological mechanisms involving inflammation, epicardial adipose tissue (EAT) accumulation, and electrical cardiac remodeling. EAT is a predictor for AF as it may induce its onset through direct (infiltration of epicardial adipocytes into the underlying atrial myocardium) and indirect (release of inflammatory adipokines, the stimulation of oxidative stress, macrophage phenotype switching, and AF triggers) mechanisms. Classic RAS blockers such as angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) may prevent AF by affecting the accumulation of the EAT, representing a useful therapeutic strategy for preventing AF especially in patients with heart failure and known left ventricular dysfunction. Further studies are necessary to prove this benefit in patients with other cardiovascular diseases. Finally, the possibility of using the A1-7 or ACE2 analogues, to enlarge current therapeutic options for AF, may represent an important field of research.
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Angiotensina II/metabolismo , Angiotensina I/metabolismo , Fibrilação Atrial/metabolismo , Remodelamento Atrial , Fragmentos de Peptídeos/metabolismo , Fibrilação Atrial/fisiopatologia , HumanosRESUMO
There was a mistake in Prof. Giuseppe Massimo Claudio Rosano's affiliation.
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WHAT IS KNOWN AND OBJECTIVE: Medication errors, such as unnecessary treatment discontinuation during treatment with direct-acting antivirals (DAAs), can lead to imbalances in the benefit-to-risk ratio. This risk is especially high when the medication error leads to adverse drug reactions (ADRs). However, to date, evidence on the frequency of this phenomenon is scarce. This study aims to provide better insight into ADRs possibly due to medication errors leading to DAA discontinuation and their preventability. METHODS: The Italian Pharmacovigilance Network database was used to extract individual case safety reports (ICSRs) generated from July 2012 to March 2017 via the Campania Region (Italy) spontaneous reporting system. ICSRs that included ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir, dasabuvir, daclatasvir, sofosbuvir, simeprevir or elbasvir/grazoprevir as suspected drugs were included in this study. A preventability assessment was then performed utilizing the "P-Method," an algorithm that evaluates known risk factors due to medication errors that can be detected in ICSRs. RESULTS AND DISCUSSION: Of the 355 cases included in this study, 6 (1.69%) were classified as preventable and 52 (14.6%) were classified as potentially preventable. The most frequently identified critical criteria (risk factor) for preventable or potentially preventable cases were drug-drug interactions and incorrect drug dosing as part of the antiviral treatment scheme. In total, 89 of the 355 cases (25.1%) discontinued use of the DAAs due to ADRs, of which 20 of the 89 cases (22.5%) were due to an unimportant medical event as classified by the European Medicine Agency important medical event list. WHAT IS NEW AND CONCLUSION: This study found a proportion of preventable/potentially preventable ADRs involving DAA, which could be improved in the Campania Region (Italy). Additionally, the study identified a high proportion of seemingly unnecessary DAA discontinuations among patients who experienced ADRs.
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Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Antivirais/administração & dosagem , Hepatite C/tratamento farmacológico , Erros de Medicação/estatística & dados numéricos , Idoso , Algoritmos , Antivirais/efeitos adversos , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Itália , Masculino , Erros de Medicação/prevenção & controle , Pessoa de Meia-Idade , Farmacovigilância , Fatores de RiscoRESUMO
Little is known about the development of psychosis during hydroxychloroquine (HCQ) treatment, especially in elderly patients affected by rheumatic diseases, with multiple comorbidities and treatments. To summarize the available evidence on HCQ-induced psychosis in elders, we performed a literature review. Additionally, individual case safety reports sent to the European Pharmacovigilance database (EudraVigilance) with HCQ as suspected drug and related to adverse events belonging to the System Organ Class 'Psychiatric disorders' were shown. Over the years, evidence was published about the risk of neuropsychiatric clinical manifestations during HCQ treatment for rheumatic diseases, but few of them were related to elderly patients. These adverse events can include less severe clinical manifestations such as affect lability and nervousness or more severe conditions such as actual psychosis and suicidal tendencies, which frequency are actually unknown. The presence of risk factors in these patients may precipitate HCQ-induced psychosis and their precocious detection could be associated with a risk minimization. Among predisposing risk factors, there are the co-exposure to interacting drugs, alcohol intake, familial history of psychiatric diseases, female gender, and the concomitant use of low-dose glucocorticoids. In some cases it was possible to reverse psychotic behaviour with the antipsychotic treatment or with HCQ suspension.
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Hidroxicloroquina/efeitos adversos , Humanos , Hidroxicloroquina/farmacocinética , Vigilância de Produtos Comercializados , Psicoses Induzidas por Substâncias/etiologia , Fatores de RiscoRESUMO
Causality assessment is a fundamental biomedical technique for the signal detection performed by Pharmacovigilance centers in a Spontaneous reporting system. Moreover, it is a crucial and important practice for detecting preventable adverse drug reactions. Among different methods for causality assessment, algorithms (such as the Naranjo, or Begaud Methods) seem for their operational procedure and easier applicability one of the most commonly used methods. With the upcoming of the new European Pharmacovigilance legislation including in the definition of the adverse event also effects resulting from abuse, misuse and medication error, all well-known preventable causes of ADRs, there was an emerging need to evaluate whether algorithms could fulfill this new definition. In this review, twenty-two algorithmic methods were identified and none of them seemed to fulfill perfectly the new criteria of adverse event although some of them come close. In fact, several issues were arisen in applying causality assessment algorithms to these new definitions as for example the impossibility to answer the rechallenge question in case of medication error or AEFI (Adverse Event Following Immunization). Moreover, the exact conditions at which events occurred, as for example dosage or mode of administration should be considered to better assess causality in conditions of abuse/overdose, or misuse as well as in conditions of lack of expected efficacy reports for biotechnological drugs and adverse event occurring after mixing of vaccines. Therefore, this review highlights the need of updating algorithmic methods to allow a perfect applicability in all possible clinical scenarios accordingly or not with the terms of marketing authorization.
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Algoritmos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Europa (Continente) , Humanos , Vigilância de Produtos ComercializadosRESUMO
BACKGROUND: A potential risk of suicide associated with liraglutide or semaglutide treatments has recently emerged. Therefore, we decided to investigate the reporting probability of suicidal events among glucagon-like peptide-1 receptor agonists (GLP-1 RAs). METHODS: A retrospective pharmacovigilance study of the European Pharmacovigilance database was conducted for the period from 1 January 2018 to 10 July 2023. Disproportionality analyses (reporting odds ratio, ROR) were performed to assess the reporting probability of suicidal events among GLP-1 RAs. RESULTS: A total of 230 reports of suicidal events were identified. The most reported GLP-1 RA was liraglutide (38.3%), followed by semaglutide (36.5%) and dulaglutide (16.1%). The most reported events were suicidal ideation (65.3%) and suicide attempt (19.5%). Disproportionality analysis found a higher reporting probability of suicidal events for semaglutide than dulaglutide (ROR, 2.05; 95%CI, 1.40-3.01) and exenatide (ROR, 1.81; 95%CI, 1.08-3.05). In the same way, liraglutide was associated with a higher reporting probability of suicidal events than dulaglutide (ROR, 3.98; 95%CI, 2.73-5.82) and exenatide (ROR, 3.52; 95%CI, 2.10-5.92). On the contrary, a lower reporting probability was found for semaglutide than liraglutide (ROR, 0.51; 95%CI, 0.38-0.69). CONCLUSIONS: Suicidal events were mostly reported with semaglutide and liraglutide, which were also associated with significantly higher reporting probabilities compared to other GLP1 RAs. Although this study provides the reporting frequencies of suicide-related events with GLP-1 RAs, establishing causality requires further investigation, which will probably be addressed by the Pharmacovigilance Risk Assessment Committee of the European Medicine Agency in the future.
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BACKGROUND: Compassionate drug use (CDU) provides early access to not yet authorised medicines and is funded by pharmaceutical companies. The observational retrospective study Compass-O monitored the CDU of onco-haematological drugs, managed by seven Italian units for cytotoxic drug preparations (Unità Farmaci Antiblastici [UFA]), between 1 January, 2016 and 31 December, 2021. OBJECTIVE: We aimed to evaluate the CDU of onco-haematological drugs managed by seven Italian UFA, between 2016 and 2021. METHODS: The seven UFA provided anonymised data concerning CDU approved in the study period. The early access and potential cost savings for the National Health System (Servizio Sanitario Nazionale [SSN]) were analysed for CDU concerning drug-therapeutic indication combinations with complete data and reimbursed by SSN up to December 2023 (date of study execution), according to the executive decision of the Italian Medicines Agency (Agenzia Italiana del Farmaco [AIFA]). Both analyses distinguished solid/liquid tumours and categorised the combinations as innovative (fully/conditionally) or non-innovative based on AIFA assessments. RESULTS: Compass-O collected 783 CDU authorisations, with 572 (73.1%) analysable in terms of early access and cost savings. On average, early access amounted to 514 days and the total cost savings was 376,115,801. Compassionate drug use approvals involved mainly solid tumours (93.7% vs 6.3% for liquid tumours), and the combination of trastuzumab emtansine-breast cancer was the most dispensed (n = 73; early access = 426 days; potential cost savings: 610,388). Out of 572 CDU approvals, 200 (35%) were innovative drug-therapeutic indication combinations, with 598 days of early access and a total potential saving of 113,124,069. CONCLUSIONS: The study Compass-O showed a significant economic burden of CDU and a relevant need for early access, particularly for innovative drugs. However, there is currently no structured monitoring of CDU in Italy, suggesting the need for a national observatory, of which Compass-O can be the pilot phase.
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Background: Acquired aplastic anemia (AAA) in pediatric patients is a rare disorder characterized by hypocellular bone marrow and pancytopenia. Eltrombopag, an oral thrombopoietin receptor agonist, provides a hematologic improvement in adults with severe aplastic anemia (SAA) refractory to immunosuppressive therapy (IST). The association of ELT and IST was approved by the US Food and Drug Administration (FDA) for adults and children ≥2 years of age as a first-line treatment for SAA. However, the effects of ELT on pediatric patients with SAA remain controversial and limited. Methods and findings: We conducted a systematic review of the most recent literature from Pubmed, Web of Science, and Embase, published up to 20th December 2022, in order to evaluate the available evidence on the efficacy and safety of ELT added to IST for the treatment of SAA in the pediatric population. Conclusion: Eltrombopag added to the IST has shown a good safety profile, without manifestations of excessive toxic effects, although not all the results obtained from our studies support the addition of ELT to the IST in the first-line treatment of children with SAA. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022325859.
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The ESCMID-EUCIC guideline on decolonization of multidrug-resistant Gram-negative bacteria carriers does not recommend routine decolonization and highlights the necessity of well-powered and designed randomized clinical trials. Based on this limited evidence, we decided to conduct a scoping review with the aim of describing and discussing the last published studies investigating the efficacy and safety of decolonization therapies in drug-resistant Enterobacteriaceae carriers. Studies published in PubMed from January 1, 2017 to December 28, 2021 were retrieved. A PICO (population, intervention, comparator, outcome) framework was used for article selection as follows: Population defined as any patient of any age in any setting with screening sample yielding for drug-resistant Enterobacteriaceae; Intervention defined as any decolonization; Controls defined as patients receiving no intervention (spontaneous decolonization) or a different decolonization therapy; Outcomes defined as a microbiological, clinical, epidemiological and adverse event. A total of 679 records were initially identified, of which 647 were excluded because they were not related to decolonization therapies. Other 18 records were excluded because not related to our aims, target bacteria, or study design. A total of 12 clinical studies were included, of which 4 were randomized clinical trials and 8 were non-randomized studies. The majority of studies evaluated selective decontamination of the digestive tract or selective oropharyngeal decontamination regimens. Selected studies were characterized by high heterogeneity. Further high-quality studies with proper design and sample size calculation are warranted.
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Infecções por Enterobacteriaceae , Enterobacteriaceae , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Trato Gastrointestinal/microbiologia , Bactérias , Infecções por Enterobacteriaceae/epidemiologiaRESUMO
Tixagevimab-cilgavimab is effective for the treatment of early COVID-19 in outpatients with risk factors for progression to severe illness, as well as for primary prevention and post-exposure prophylaxis. We aimed to retrospectively evaluate the hospital stay (expressed in days), prognosis, and negativity rate for COVID-19 in patients after treatment with tixagevimab-cilgavimab. We enrolled 42 patients who were nasal swab-positive for SARS-CoV-2 (antigenic and molecular)-both vaccinated and not vaccinated for COVID-19-hospitalized at the first division of the Cotugno Hospital in Naples who had received a single intramuscular dose of tixagevimab-cilgavimab (300 mg/300 mg). All patient candidates for tixagevimab-cilgavimab had immunocompromised immune systems either due to chronic degenerative disorders (Group A: 27 patients) or oncohematological diseases (Group B: 15 patients). Patients enrolled in group A came under our observation after 10 days of clinical symptoms and 5 days after testing positivite for COVID-19, unlike the other patients enrolled in the study. The mean stay in hospital for the patients in Group A was 21 ± 5 days vs. 25 ± 5 days in Group B. Twenty patients tested negative after a median hospitalization stay of 16 days (IQR: 18-15.25); of them, five (25%) patients belonged to group B. Therefore, patients with active hematological malignancy had a lower negativization rate when treated 10 days after the onset of clinical symptoms and five days after their first COVID-19 positive nasal swab.
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(1) Background: The purpose of study was to compare the safety profile of glatiramer with natalizumab, alemtuzumab and ocrelizumab in pregnant and lactating women affected by multiple sclerosis (MS). (2) Methods: Individual case safety reports (ICSRs) were retrieved from the European spontaneous reporting system database (EudraVigilance). The reporting odds ratios (RORs) were computed to compare the reporting probability of events between natalizumab, alemtuzumab and ocrelizumab vs. glatiramer. (3) Results: A total of 1236 ICSRs reporting at least one DMT as a suspected drug were selected. More adverse drug reactions (ADRs) unrelated to pregnancy and breastfeeding (n = 1171; 32.6%) were reported than ADRs specific to pregnancy and breastfeeding (n = 1093; 30.4%). The most frequently reported unrelated ADR was MS relapse. Alemtuzumab and natalizumab seem to have a lower reporting probability of MS relapse compared to glatiramer (ROR 0.17, 95% CI 0.07-0.45 and ROR 0.34, 95% CI 0.20-0.57). Among pregnancy- and breastfeeding-related ADRs, the first most reported event was spontaneous abortion (n = 321; 8.9%). Natalizumab and ocrelizumab were associated with a higher reporting probability of spontaneous abortion compared to glatiramer (ROR 2.22, 95% CI 1.58-3.12; ROR 2.18, 95% CI 1.34-3.54, respectively), while alemtuzumab had a lower reporting frequency (ROR 0.32, 95% CI 0.17-0.60). (4) Conclusions: This study did not suggest any strong or new insights for DMTs in this special subpopulation. However, further studies need to be performed.
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Chemotherapy represents the main pharmacological cancer treatment. Recently, positive effects emerged with the combination of anticancer therapy and nutraceutical products. The aim of this systematic review is to collect and synthesize the available scientific evidence regarding the potential effects of nutraceuticals on cancer cells. A systematic literature search of randomized clinical trials of nutraceutical products in patients with cancer published up to 15 December 2022 was conducted using three data sources: Embase, PubMed, and Web of Science. The effect of high-dose isoflavone supplements on prostate cancer resulted in stabilization or reduction of PSA concentrations in 50% of isoflavone group patients six months after treatment. High doses of vitamin D supplementation plus chemotherapy in patients with advanced or metastatic colorectal cancer showed a median PFS of 13.0 months (95% CI, 10.1-14.7 months) for 49 patients. The effect of vitamin D supplementation on markers of inflammatory level and antioxidant capacity in women with breast cancer showed a significant increase in serum vitamin D concentration (28 ± 2.6 to 39 ± 3.5; p = 0.004) after 8 weeks of treatment. In conclusion, nutraceutical supplements represent a potentially growing sector and can be utilized in medical treatment or nutrition to provide integrated medical care.
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Neoplasias , Vitaminas , Masculino , Humanos , Feminino , Ensaios Clínicos Controlados Aleatórios como Assunto , Suplementos Nutricionais , Vitamina D , Antioxidantes/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/induzido quimicamenteRESUMO
Introduction: Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is authorized for the treatment of chronic lymphocytic leukemia (CLL). This study aims to explore the cardiac safety profile of ibrutinib in comparison with obinutuzumab. Methods: A retrospective pharmacovigilance study was conducted on data retrieved from the European pharmacovigilance database (Eudravigilance) from 1 January 2014 to 30 September 2022. To compare the reporting frequency of cardiovascular events among ibrutinib, obinutuzumab, and the combination of both. Results: A total of 2 291 CV cases were retrieved, of which 1965 were related to ibrutinib, 312 to obinutuzumab, and 14 to the combination. Most cases referred to patients aged ≥65 years (N = 1,454; 63.47%) and male (N = 1,497; 65.34%). Most cases were serious (N = 2,131; 93.02%). The most reported events were: atrial fibrillation (N = 913; 31.31%) and haemorrhage (N = 201; 6.89%). A higher reporting frequency of CV events was found when ibrutinib was compared to obinutuzumab (ROR, 3.22; 95% CI, 2.89-3.60) or combination (ROR, 1.77; 95% CI, 1.11-2.83). A lower reporting was observed when obinutuzumab was compared to combination (ROR, 0.55; 95% CI, 0.34-0.88). Discussion: A higher reporting frequency of CV events in patients exposed to ibrutinib in comparison with obinutuzumab was found. Further studies are needed to better explore the safety of ibrutinib.
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BACKGROUND: Despite the available evidence showing an association between cardiac arrhythmia and Immune Checkpoint Inhibitors (ICIs), few studies have compared this risk between ICIs. OBJECTIVES: We aim to evaluate Individual Case Safety Reports (ICSRs) of ICIs-induced cardiac arrhythmias and compare the reporting frequency of cardiac arrhythmias among ICIs. METHODS: ICSRs were retrieved from the European Pharmacovigilance database (Eudravigilance). ICSRs were classified based on the ICI reported (pembrolizumab, nivolumab, atezolizumab, ipilimumab, durvalumab, avelumab, cemiplimab, and dostarlimab). If more than one ICI was reported, the ICSR was classified as a combination of ICIs. ICSRs of ICI-related arrhythmias were described and the reporting frequency of cardiac arrhythmias was assessed by applying the reporting odds ratio (ROR) and its 95 % confidence interval (95 %CI). RESULTS: A total of 1262 ICSRs were retrieved, of which 147 (11.65 %) were related to combinations of ICIs. A total of 1426 events of cardiac arrhythmias were identified. The three most reported events were atrial fibrillation, tachycardia, and cardiac arrest. Ipilimumab was associated with a reduced reporting frequency of cardiac arrhythmias compared to all other ICIs (ROR 0.71, 95 %CI 0.55-0.92; p = 0.009). Anti-PD1 was associated with a higher reporting frequency of cardiac arrhythmias than anti-CTLA4 (ROR 1.47, 95 %CI 1.14-1.90; p = 0.003). CONCLUSION: This study is the first comparing ICIs for the risk of cardiac arrhythmias. We found that ipilimumab was the only ICI associated with a reduced reporting frequency. Further high-quality studies are needed to confirm our results.
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Antineoplásicos Imunológicos , Fibrilação Atrial , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Ipilimumab , FarmacovigilânciaRESUMO
Background: The risk of falls and bone fractures with sodium-glucose co-transporter-2 (SGLT2) inhibitors has been characterized by conflicting evidence. Therefore, we decided to investigate the reporting probability of falls and fractures by comparing SGLT2 inhibitors with DPP4 inhibitors. Methods A retrospective, pharmacovigilance study of the European database of Individual Case Safety Reports (ICSRs) was conducted. Disproportionality analyses (Reporting Odds Ratio, ROR) were conducted to compare the reporting probability of falls or fracture between treatments. Results A total of 507 ICSRs reporting at least one fall or fracture with SGLT2 inhibitors were identified. The most reported SGLT2 inhibitor was canagliflozin (N = 188; 36.9%), followed by empagliflozin (N = 176; 34.5%), and dapagliflozin (N = 143; 28.0%). A total of 653 events related to fall or bone fracture were reported. Fall was the most reported event (N = 333; 51.0%). Among fractures (N = 320; 49.0%), the most reported were foot fractures (N = 40; 6.1%) and hip fractures (N = 32; 4.9%). SGLT2 inhibitors were associated with a lower reporting probability of fall than DPP4 inhibitors (ROR, 0.66; 95%CI, 0.57-0.78). The lower reporting probability of fall was also observed when the single SGLT2 inhibitor was compared to DPP4 inhibitors: dapagliflozin (ROR, 0.67; 95%CI, 0.53-0.83), canagliflozin (ROR, 0.56; 95%CI, 0.45-0.70), and empagliflozin (ROR, 0.77; 95%CI, 0.63-0.94). For fractures, canagliflozin showed a slightly significant increased reporting when compared with DPP4 inhibitors (not confirmed in the sensitivity analysis), whereas all other comparison showed no statistically significant difference. Conclusion SGLT2 inhibitors were associated with a lower reporting probability of fall than DPP4 inhibitors, in accordance with the reassuring evidence about the safety profile of these drugs. Future researches will help to confirm their long-term safety profile.
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Atrial fibrillation (AF) has been described in COVID-19 patients. Recently, some case reports and US pharmacovigilance analyses described AF onset as a rare adverse event following COVID-19 vaccination. The possible correlation is unclear. We systematically analyzed the reports of AF related to COVID-19 vaccines collected in the European pharmacovigilance database, EudraVigilance (EV), from 2020 to November 2022. We carried out descriptive and disproportionality analyses. Moreover, we performed a sensitivity analysis, excluding the reports describing other possible alternative AF causes (pericarditis, myocarditis, COVID-19, or other drugs that may cause/exacerbate AF). Overall, we retrieved 6226 reports, which represented only 0.3% of all those related to COVID-19 vaccines collected in EV during our study period. AF reports mainly referred to adults (in particular, >65 years old), with an equal distribution in sex. Reports were mainly related to tozinameran (54.04%), elasomeran (28.3%), and ChAdOx1-S (14.32%). The reported AF required patient hospitalization in 35% of cases and resulted in a life-threatening condition in 10% of cases. The AF duration (when reported) was highly variable, but the majority of the events had a short duration (moda = 24 h). Although an increased frequency of AF reporting with mRNA vaccines emerges from our study, other investigations are required to investigate the possible correlation between COVID-19 vaccination and the rare AF occurrence.