Decoding adverse event signals of folic acid supplementation in cardiac patients: a stratified pharmacovigilance analysis based on FAERS

Background: Folic acid is widely used in cardiovascular care, yet real-world adverse event (AE) profiles in cardiac patients remain incompletely characterized. We evaluated folic-acid–associated AEs reported during treatment of cardiac disorders. Methods: We analyzed the FDA Adverse Event Reporting System (FAERS) from January 1, 2004 to January 1, 2025. Reports were eligible when folic acid was a primary or secondary suspect drug and the indication involved cardiac disorders (MedDRA HLGT under the System Organ Class “Cardiac disorders”). Signals were screened using reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and empirical Bayesian geometric mean. Preferred terms with ≥20 reports were examined in depth. Analyses were stratified by age (18–64, 65–84, and ≥85 years) and sex. Time-to-onset was assessed using Kaplan–Meier and Weibull models. Results: Among 532 patients, 509 AEs were co-reported with folic acid in the context of cardiac disorders. Disproportionality analyses identified 147 AE signals; 20 PTs with ≥20 reports were examined in depth. The most frequently reported PTs were pyrexia (7.0%), obstructive airway disease (4.3%), diaphragmatic disorder (4.2%), pancytopenia (3.1%), and rash (2.9%). Most moderate-priority AEs occurred within 2 months of therapy initiation (renal/urinary AEs within 2 years), and Weibull β-values >1 across System Organ Classes suggested increasing hazard over time. Adults aged 18–64 years had more musculoskeletal and vitamin B12-related signals, whereas patients ≥65 years had more neurological and renal toxicities; sex differences were modest. Conclusions: FAERS reports suggest a diverse, time-dependent AE spectrum potentially associated with folic acid use in cardiac patients, with greater vulnerability in older adults. Findings are hypothesis-generating and warrant confirmation in prospective studies.