Use of Disproportionality Analysis to Identify Previously Unknown Drug-Associated Causes of Cardiac Arrhythmias Using the Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

Introduction: Drug-induced QT-prolongation is a well-known adverse drug reaction (ADR), however there is limited knowledge of other drug-induced arrhythmias.

Purpose: The objective of this study is to determine the drugs reported to be associated with arrhythmias other than QT-prolongation using the FAERS database, possibly identifying potential drug causes that have not been reported previously.

Methods: FAERS reports from 2004 quarter 1 through 2019 quarter 1 were combined to create a dataset of approximately 11.6 million reports. Search terms for arrhythmias of interest were selected from the Standardized MedDRA Queries (SMQ) Version 12.0. Frequency of the cardiac arrhythmias were determined for atrial fibrillation, atrioventricular block, bradyarrhythmia, bundle branch block, supraventricular tachycardia, and ventricular fibrillation and linked to the reported causal medications. Reports were further categorized by prior evidence associations using package inserts and established drug databases. A reporting odds ratio (ROR) and confidence interval (CI) were calculated for the ADRs for each drug and each of the 6 cardiac arrhythmias.

Results: Of the 11.6 million reports in the FAERS database, 68,989 were specific to cardiac arrhythmias of interest. There were 61 identified medication-reported arrhythmia pairs for the 6 arrhythmia groups with 33 found to have an unknown reported association. Rosiglitazone was the most frequently medication reported across all arrhythmias [ROR 6.02 (CI: 5.82-6.22)]. Other medications with significant findings included: rofecoxib, digoxin, alendronate, lenalidomide, dronedarone, zoledronic acid, adalimumab, dabigatran, and interferon beta-1b.

Conclusion: Upon retrospective analysis of the FAERS database, the majority of drug-associated arrhythmias reported were unknown suggesting new potential drug causes. Cardiac arrhythmias other than QTc prolongation are a new area of focus for pharmacovigilance and medication safety. Consideration of future studies should be given to using the FAERS database as a timely pharmacovigilance tool to identify unknown adverse events of medications.