Expert Opinion on Drug Safety最新文献

Background: There is conflicting real-world evidence regarding the risk of breast and bladder cancer associated with sodium glucose cotransporter 2 (SGLT2) inhibitors. We conducted a pharmacovigilance study on SGLT2 inhibitors and breast and bladder cancer using the US FDA Adverse Event Reporting System (FAERS) and a Mendelian randomization (MR) study.

Research design and methods: We used AERSMine to mine adverse events from FAERS. We provided proportional reporting ratio (PRR) with 95% confidence interval (CI), and the lower limit of the 95% credible interval of the information component (IC₀₂₅). A two-sample MR approach was used to investigate the causal relationship between SGLT2 inhibition and breast and bladder cancer.

Results: We did not find a disproportionate association between SGLT2 inhibitors (PRR = 1.26; 95%CI 1.05-1.51; p = 0.014; IC₀₂₅ = 0.01) and their molecules with breast cancer. SGLT2 inhibitors were associated with a disproportionately higher reporting frequency of bladder cancer events compared to metformin, dipeptidyl peptidase 4 inhibitors, or glucagon-like peptide-1 receptor agonists. MR analysis results showed that SGLT2 inhibition was associated with a higher risk of bladder cancer (odds ratio 1.01; 95%CI 1.00-1.01; p = 0.004).

Conclusion: Our results suggest that the use of SGLT2 inhibitors is associated with a higher reporting frequency/risk of bladder cancer, rather than breast cancer.

Introduction: Advanced chronic kidney disease (CKD), defined as an estimated glomerular filtration rate < 30 ml/min/1.73 m², significantly amplifies the challenges of managing atrial fibrillation (AF), highly prevalent in this population. People with advanced CKD besides increased cardiovascular risk are also at increased risk of both thromboembolic events and bleeding complications. Evidence regarding optimal anticoagulants use in this specific population remains limited, as most pivotal trials exclude people with advanced CKD, also those on maintenance dialysis.

Areas covered: This review examines the safety and efficacy of anticoagulation strategies, namely vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) in people with AF and advanced CKD. It highlights the shortcomings of existing thromboembolism risk stratification tools and explores the off-target effects of anticoagulants. The literature search utilized PubMed, Embase, and Web of Science.

Expert opinion: Some emerging data suggest that DOACs, particularly rivaroxaban and apixaban, may offer improved safety profiles compared to VKA in advanced CKD, with comparable efficacy. Observational studies indicate a potential advantage of DOACs in preventing stroke or systemic embolism (SSE) over VKA. Large clinical trials including a non-anticoagulation arm and validation of risk stratification tools specific to advanced CKD are urgently needed.

Background: This study conducts a comprehensive comparative analysis of adverse event (AE) signals between sacubitril/valsartan and valsartan, two pivotal cardiovascular drugs for heart failure and hypertension, utilizing the FAERS database to identify differential safety risks and optimize clinical monitoring.

Research design and methods: Data from the FAERS database (2004Q1-2024Q2) were analyzed using disproportionality analysis and Bayesian methods to detect and evaluate AE signals associated with sacubitril/valsartan and valsartan, enabling a comparative assessment.

Results: A total of 102,678 adverse event reports (AERs) were linked to sacubitril/valsartan, compared to 24,318 AERs for valsartan. Sacubitril/valsartan demonstrated the strongest association with cardiac disorders (ROR 4.13), while valsartan exhibited the highest association with vascular disorders (ROR 2.67). Common AE signals aligned with the respective drug labels. Unexpected AEs for sacubitril/valsartan included myocardial infarction (n = 2,909, ROR 6.45), arrhythmia (n = 1,691, ROR 4.07), decreased activity (n = 544, ROR 11.13), and fluid imbalance (n = 44, ROR 11.98). Unique AEs for valsartan included fear of disease (n = 137, ROR 47.57), thrombotic stroke (n = 31, ROR 25.60), merycism (n = 30, ROR 79.41), and eosinophilic colitis (n = 11, ROR 20.62).

Conclusions: Sacubitril/valsartan and valsartan exhibit distinct AE risk profiles in cardiovascular disease treatment, underscoring the need for large-scale clinical trials and mechanistic studies on sacubitril to validate these findings.

Introduction: Placental abruption is a significant cause of fetomaternal mortality/morbidity. Management requires a difficult balance between opposing advantages/disadvantages for the fetus and mother. Remote from term, prompt delivery is best for the mother, but delayed delivery better for the fetus.

Areas covered: Prevalence of fetomaternal morbidity/mortality; range of clinical situations: certainty of diagnosis, gestational age, labor status, fetal condition/viability, presence of maternal shock/consumption coagulopathy, feasibility of prompt delivery. Pathophysiology: maternal hypovolaemia; abruption size; impairment of placental oxygenation; intrauterine tone and pressure; safety, efficacy, and application of tocolytic therapy to abruption; potential role of atosiban with emphasis on safety.

Expert opinion: The fetomaternal morbidity/mortality of placental abruption deserves consideration of further interventions that may improve fetomaternal outcome. More information is now available about signs/symptoms that do not require invasive diagnostic procedures. The contribution of maternal uterine hypertonus/tachysystole and increased uterine tone/pressure that affects fetal hypoxia/acidosis and consumption coagulopathy, strengthens the case for the use of a tocolytic to relax the uterus and improve fetal oxygenation. Due to its safety and efficacy profile, we make the case for atosiban as an agent to reduce uterine contractile frequency, tone, and pressure to improve fetal oxygenation and improve fetomaternal outcome.

Introduction: The United States Food and Drug Administration (FDA) requires post-marketing surveillance of approved drugs, and pharmaceutical manufacturers maintain comprehensive programs that include adverse event monitoring, internal safety assessments, and reporting to the FDA Adverse Events Reporting System (FAERS).

Areas covered: This report provides an overview of FAERS within the broader framework of post-marketing surveillance by pharmaceutical manufacturers. It also identifies several limitations to FAERS public dashboard data for safety analyses. A PubMed search for published findings of FAERS safety analyses with vesicular monoamine transporter 2 (VMAT2) inhibitors provide a case study that illustrates the need for careful interpretation based on the limitations of the FAERS database.

Expert opinion: Using a case study of VMAT2 inhibitors, we identified factors in data quality and manufacturer pharmacovigilance programs that must be considered when interpreting published analyses of FAERS public safety data. The application of artificial intelligence methodologies may prove helpful in identifying novel safety signals more accurately and more rapidly. At the same time, as clinicians consider individual treatment choices with their patients, discussion of safety data from the FAERS public dashboard should be contextualized within each drug's known safety profile.

Introduction: In patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention, 12 months of dual antiplatelet therapy (DAPT) with aspirin plus a P2Y₁₂ inhibitor is the current standard. However, DAPT is associated with an increased risk of bleeding. DAPT duration and intensity should be modulated according to the patient's specific risk profile to optimize outcomes.

Areas covered: Different DAPT regimens varying in intensity and duration have been shown to improve outcomes in specific settings. In patients at increased ischemic risk, DAPT escalation or prolongation can be considered, while de-escalation by discontinuing one of the antiplatelet drugs, reduction in the dose of the P2Y₁₂ inhibitor, or switching to a less potent P2Y₁₂ inhibitor should be considered in patients at increased risk of bleeding. Platelet function and genetic testing may help guiding the decision making. Antiplatelet agents also have specific drug-related adverse effects that clinicians should be aware of.

Expert opinion: Management of ACS patients has largely shifted over time, in order to achieve a patient-oriented approach. Development of specific scores based on genetic and clinical characteristics to predict patient's responsiveness to clopidogrel may allow to further reduce ischemic events, while technological and pharmacological advances are paving the way for further reduction of bleeding risk while preserving efficacy.