# Disproportionality analysis of adverse events associated with endothelin receptor antagonists based on the FDA adverse event reporting system (FAERS)

## TL;DR

This study analyzed real-world safety data of three drugs used to treat pulmonary arterial hypertension to identify common and new side effects.

## Contribution

The study provides novel insights into the comparative safety profiles of endothelin receptor antagonists using FAERS data and multiple signal detection algorithms.

## Key findings

- Ambrisentan had the highest proportion of reported adverse drug events compared to other ERAs.
- Novel signals such as jaw pain, pulmonary thrombosis, and hypotension were identified alongside known side effects.
- Most adverse events occurred within the first year of treatment, emphasizing the need for early monitoring.

## Abstract

Endothelin receptor antagonists (ERAs), including bosentan, ambrisentan, and macitentan, are recognized as first-line treatments for pulmonary arterial hypertension (PAH). Although their therapeutic efficacy is well established, variations in receptor selectivity and metabolic pathways may lead to distinct adverse drug event (ADE) profiles. Nonetheless, large-scale, real-world comparative safety data remain limited. As part of routine pharmacovigilance activities, we analyzed data from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) to identify disproportionate reporting signals.

This study leveraged data from FAERS to identify and compare potential ADEs associated with bosentan, ambrisentan, and macitentan, thereby facilitating safer and more informed clinical decision-making in pharmacotherapy.

A disproportionality analysis of individual case safety reports (ICSRs) from the FAERS was performed for the period spanning Q1 2004 to Q2 2025. The classification of ADEs was conducted utilizing the Medical Dictionary for Regulatory Activities (MedDRA®) terminology. Signal detection was executed employing four distinct algorithms: the Reporting Odds Ratio (ROR), the Proportional Reporting Ratio (PRR), the Bayesian Confidence Propagation Neural Network (BCPNN), and the Multi-item Gamma Poisson Shrinker (MGPS), all based on an observational and retrospective proportional imbalance analysis of the FAERS database. Additionally, a Time-to-Onset (TTO) analysis was conducted to evaluate the temporal distribution of ADEs.

A total of 35,112, 48,411, and 29,877 ADE reports were collected for bosentan, ambrisentan, and macitentan, respectively. The majority of reports originated from female patients, with a male-to-female ratio of 1:2.91, aged between 18 and 65 years. Ambrisentan was disproportionally more frequently reported the highest incidence of ADEs, accounting for 42.69% of cases. Significant ADE signals were identified in the hepatobiliary, hematologic, cardiovascular, respiratory, and fluid retention-related categories. The observed ADEs predominantly comprised peripheral edema, dyspnea, liver function abnormalities, and anemia, consistent with the documented drug labeling. It is crucial that novel signals were identified, including jaw pain, pulmonary thrombosis, gout, decreased blood potassium, and hypotension. TTO analysis revealed that the majority of ADEs occurred within the first year of treatment.

This study corroborated the established ADEs associated with ERAs and identified novel ADE signals, thereby providing new insights into their safety profile. The findings emphasize the importance of comprehensive monitoring of hepatic function, blood pressure, renal function, and electrolyte levels during ERA treatment. These results provide valuable insights for clinicians aiming to optimize ERA utilization, minimize associated risks, and improve patient outcomes. Future research should focus on elucidating the underlying mechanisms of these ADEs to further enhance the safety and efficacy of ERA therapies.