Real-World Pharmacovigilance Analysis of Drug-Induced Decreased Cardiac Ejection Function: Evidence from the FAERS Database (2004-2024).

Abstract

Introduction: Decreased Cardiac Ejection Function (DCEF) is a critical manifestation of cardiotoxicity and has been increasingly recognized as a potential adverse effect of pharmacotherapy, particularly with antineoplastic and immunomodulating agents. This study conducted a comprehensive pharmacovigilance assessment of drug-induced DCEF using the FDA Adverse Event Reporting System (FAERS), focusing on high-risk drug identification, onset timing, and pharmacological classification.

Methods: FAERS reports from 2004 to 2024 were standardized using MedDRA and RxNorm. Disproportionality analysis with Reporting Odds Ratios (ROR) and 95% Confidence Intervals (CI) was used to detect drug-event associations. Time-to-Onset (TTO) analysis was performed for five clinically relevant agents, doxorubicin, docetaxel, rituximab, dabrafenib, and bevacizumab, selected based on frequency, signal strength, and clinical importance. Weibull modeling was used to characterize temporal risk patterns.

Results: A total of 86 drugs were significantly associated with DCEF. Frequently reported agents included trastuzumab (1,183 cases) and doxorubicin (465 cases). Notably, 50 drugs (e.g., clozapine, rofecoxib, docetaxel) were not previously labeled for DCEF, representing novel safety signals. Time-to-onset analysis showed that all five evaluated agents followed an "earlyfailure" pattern (β < 1), meaning the risk of DCEF was highest shortly after treatment initiation and declined thereafter. Median TTO ranged from 42 days for rituximab (β = 0.52, 95% CI: 0.41-0.63) to 140 days for doxorubicin (β = 0.83, 95% CI: 0.68-0.97; α = 277.8, 95% CI: 187.6-367.9), suggesting variable latency between drugs. Demographically, patients aged 65-85 years (22.9% of known cases) and those with body weight 70-89 kg (10.2%) were most frequently affected.

Conclusion: This large-scale real-world analysis identifies both established and novel DCEF risk signals, highlights heterogeneity in onset timing, and emphasizes the predominance of antineoplastic agents. Clinically, these findings suggest the need for periodic echocardiographic monitoring of left ventricular ejection fraction, particularly in patients receiving high-risk drugs such as mitoxantrone, trastuzumab, doxorubicin, and pertuzumab. Early-phase monitoring is crucial for "early-failure" agents, while extended follow-up is warranted for drugs with delayed toxicity, such as doxorubicin. These results provide actionable evidence to support individualized risk management and regulatory label updates.

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