Disproportionality analysis of atrial fibrillation associated with direct oral anticoagulants: A pharmacovigilance study using the Food and Drug Administration adverse event reporting system database
Year: 2025
Type: article
Study design: Observational Study
Abstract: INTRODUCTION Thromboembolic disorders such as venous thromboembolism, stroke, and myocardial infarction remain major health concerns worldwide.[1] For prevention and treatment, warfarin has a long history, but its limited therapeutic window and many interactions constrain its use in practice. Direct oral anticoagulants (DOACs) – including apixaban, rivaroxaban, dabigatran, and edoxaban – were introduced to overcome these challenges and are now widely prescribed.[2,3] Although considered safer alternatives, pharmacovigilance has highlighted possible unexpected adverse events. Among these, Atrial Fibrillation (AF) has emerged as a concern.[4] This analysis employed the Food and Drug Administration Adverse Event Reporting System (FAERS) data to determine whether DOACs are linked disproportionately with AF occurrences. METHODS We performed a retrospective disproportionality analysis using FAERS data from Q1 2014 to March 2025. Reports were included if a DOACs was the primary suspect drug and AF was coded as a Serious Adverse Event using the Medical Dictionary for Regulatory Activities terminology. Non Serious Adverse Events, duplicate records, and incomplete reports were excluded. Disproportionality was assessed using Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Information Component (IC), and Chi-square statistics. A strong signal was defined as ROR >2 with 95% confidence interval (CI) >1, PRR >2, Chi-square >4, and IC lower bound >0. RESULTS We identified 5262 AF cases associated with DOACs, with near equal sex distribution (51% male, 49% female). Most cases occurred in patients aged 65–85 years. Overall, DOACs showed a strong disproportionality signal with AF: ROR 7.05 (95% CI: 6.85–7.27), PRR 6.84, Chi-square 22,677, and IC 2.59. Among individual drugs, edoxaban showed the strongest association (ROR 13.03), followed by apixaban (ROR 9.23), dabigatran (ROR 8.52), dabigatran etexilate mesylate (ROR 4.59), and rivaroxaban (ROR 3.88). DISCUSSION This study identified a notable pharmacovigilance signal between DOACs use and reported AF, with edoxaban demonstrating the highest disproportionality. Importantly, this does not establish causality. Several factors may have contributed to the observed association. Patients prescribed with DOACs are often older and have comorbidities such as hypertension, diabetes, or heart failure – conditions independently associated with AF risk.[5] Moreover, patients on anticoagulants are subject to closer cardiovascular monitoring, which may increase the likelihood of AF detection and reporting compared with those not on therapy. Edoxaban’s stronger signal may partly reflect reporting bias. As a relatively newer agent, its safety profile is under heightened postmarketing surveillance, possibly increasing the sensitivity of adverse event reporting. The absence of a clear mechanism suggests confounding, yet consistent signals across DOACs warrant further investigation into their potential association with AF. Our findings are consistent with earlier disproportionality analyses from pharmacovigilance databases that reported unexpected cardiac safety signals with DOACs.[4] While these analyses do not offer incidence rates, they are useful for generating hypotheses and highlighting safety issues that warrant additional research. The major limitations of this study include underreporting, variable data quality, and the absence of denominator exposure, which restricts the estimation of absolute risk. Moreover, spontaneous reporting systems, while valuable for signal detection, often reflect reporting trends rather than true incidence, underscoring the need for complementary pharmacoepidemiological studies. Despite these limitations, the large dataset, strong statistical signals, and consistency across drugs provide meaningful evidence for ongoing clinical awareness. CONCLUSION The analysis highlights a significant disproportionality signal associating DOAC use with AF, with risk differing by agent. Although this pharmacovigilance signal necessitates further investigation, the findings alert clinicians to monitor for AF, especially in elderly or high-risk patients. Prospective studies are essential to clarify causality and safely optimize anticoagulant therapy. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Authors: K. Shambhavi, D. Chinmay, N. Ananya, M. S. Darshan, K. B. Rohith, S. Prajwal
Language: English
Subfield: Toxicology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W4417525214