Analysis of Arrhythmia Risk Associated with Antiepileptic Monotherapy and Combination Therapy
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https://doi.org/10.61705/0v4xgb60Keywords:
Drug-induced cardiotoxicity, Antiepileptic drugs (AEDs), Arrhythmias, Pharmacovigilance, FAERS database, Drug-drug interactions (DDIs), Combination therapyAbstract
Background and Objectives: Drug-related cardiotoxicity, including arrhythmia, is a significant concern in drug safety monitoring. Patients with epilepsy who use antiepileptic drugs (AEDs) long-term may have an increased risk of cardiovascular events. This study aims to evaluate the reporting of arrhythmia adverse events associated with AEDs using spontaneous reporting system data and to investigate differences in signals between monotherapy and combination therapy regimens.
Methods: A pharmacovigilance study was conducted using FAERS data from the first quarter of 2013 to the second quarter of 2023. Adverse events (AEs) related to arrhythmias were identified using standardized Medical Dictionary for Regulatory Activities (MedDRA) queries. The Reporting Odds Ratio (ROR) algorithm was employed to detect signals of arrhythmia-related AEs associated with 21 AEDs. Both monotherapy and combination therapy were analyzed, with adjustments for age, gender, indications, and concomitant medications. Additive and multiplicative models were used to assess drug-drug interactions (DDIs). Logistic regression analysis was performed to evaluate the impact of arrhythmias on mortality.
Results: A total of 1,766,899 adverse reaction reports for AED-treated patients were analyzed. Among the 21 AEDs, 19 were associated with arrhythmias, with 11 showing significant signals for arrhythmia, primarily in the form of bradyarrhythmias. The strongest signals were observed for LEV (cROR = 8.96, 95% CI: 8.64–9.29) and TGB (cROR = 5.66, 95% CI: 1.82–17.62). After adjusting for age, sex, indications, and concomitant medications, 10 drugs retained positive signals. LEV and VPA emerged as newly identified risk factors for arrhythmias. In combination therapy,166 two-drug combination therapies revealed that 14 of them exhibited significant interaction signals, particularly in combinations based on LEV or CBZ, which showed a higher number of signals. The highest interaction signals were observed in LEV+ETX (additive model = 0.0512, multiplicative model = 6.5658) and TGB+GBP (additive model = 0.0233, multiplicative model = 4.5470). Logistic regression analysis indicated that advanced age, male, and combination therapy were risk factors for arrhythmia-related mortality. The highest mortality rates were observed in combination therapies involving VPA+GBP (58.46%), TPM+CBZ (50.00%), and LEC+CZP (21.28%).
Conclusions: Comprehensive research has indicated a possible connection between antiepileptic medications and cardiac arrhythmias, which could result in significant negative effects, whether these drugs are used alone or in combination. This underscores the importance of vigilant monitoring and personalized treatment for patients receiving antiepileptic drugs in clinical settings.
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