Torsade de Pointes and QT Prolongation Among Antifungal Triazoles: A Real-World, Retrospective, Observational, Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS) Database.

The widespread use of antifungal triazoles has increasingly been associated with cardiovascular adverse events (AEs), particularly torsade de pointes (TdP) and QT prolongation. Understanding the characteristics of TdP/QT prolongation associated with antifungal triazoles is crucial for their safe and effective administration. In the FAERS database from 2004 to 2024, a total of 18,940 patients with antifungal triazoles were extracted for disproportionality analyses to reflect the degree of association between the TdP/QT prolongation and different antifungal triazoles, and the logistic regression analysis was used to identify potential influencing factors. Additionally, the study examines concomitant medication use in patients who experienced TdP/QT prolongation. Among the overall AEs cases of triazoles, the incidence rate of TdP/QT prolongation was around 2%. A disproportionality analysis indicated that antifungal triazoles were significantly associated with the occurrence of TdP/QT prolongation (reporting odds ratio (ROR) = 7.67 [7.06-8.33], p < 0.0001). Among these, isavuconazole, with the lowest ROR (ROR = 2.20 [1.10-4.40], p = 0.0257), was still significantly associated with the occurrence of TdP/QT prolongation. Based on the baseline statistical analysis of patients with AEs among triazoles, we found that compared with patients who did not develop TdP/QT prolongation, the patients with TdP/QT prolongation had significant differences in gender, types of triazoles used for treatment, administration routes, infection sites, and clinical outcomes. The results of univariate logistic regression further demonstrated that factors such as female gender (males vs. females, odds ratio (OR)[95% confidence interval (CI)] = 0.76 [0.63-0.92], p = 0.006), intravenous administration (OR [95%CI] = 3.08 [2.37-4.00], p < 0.001), abdominal and digestive system infections (OR [95%CI] = 2.88 [1.92-4.66], p < 0.001), heart and blood flow infection (OR [95%CI] = 3.33 [1.94-5.73], p < 0.001), central nervous system infection (OR[95%CI] = 3.00 [1.82-4.95], p < 0.001), and eye/ear/nose/throat and oral infections (OR [95%CI] = 1.76 [1.12-2.76], p < 0.014) increased the risk of TdP/QT prolongation among triazoles. Additionally, the occurrence of TdP/QT prolongation also increased the risk of death or life-threatening outcomes (OR[95%CI] = 2.03 [1.62-2.53], p < 0.001). Among them, patients who received intravenous medication (Intravenous vs. Oral, OR[95%CI] = 1.91 [1.13-3.22], p = 0.016) and developed target PT within 30 days (> 30 days vs. ≤ 30 days, OR [95%CI] = 0.23 [0.06-0.89], p = 0.034) had higher risks of death and life-threatening. Finally, we screened out 15 types of concomitant medications that increase the risk of TdP/QT prolongation from triazoles, including Ondansetron, Amiodarone, Levofloxacin, and etc.,which were clearly known to have the side effect of prolonging the QT interval. The TdP/QT prolongation caused by triazoles is a drug safety issue that cannot be ignored. To reduce its risk, we recommend strengthening the monitoring of patients' heart rhythms and serum electrolyte concentrations in clinical practice, especially when using intravenous administration and concomitant medication. At the same time, for high-risk patient groups, such as women, the elderly, patients with heart disease or electrolyte disorders, and patients with infections that may cause the above-mentioned lesions (such as cardiac and bloodstream infections, central nervous system infections, etc.), triazoles should be selected and used more carefully.