What question did this study set out to answer?

The study aims to identify and compare adverse drug events associated with endothelin receptor antagonists using FAERS data.

March 13, 2026Frontiers in Cardiovascular Medicine0 citationsOpen Access

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

Q: What is the clinical evidence from this study?

Study design: Observational. Population: Pulmonary Arterial Hypertension (n=113400). Intervention: Endothelin Receptor Antagonists (Bosentan, Ambrisentan, Macitentan). Primary outcome: Incidence of Adverse Drug Events (ADEs).

LHLizhu Han SLSitian Li JLJianting Liao

Key Result

Ambrisentan was disproportionately more frequently reported with ADEs, accounting for 42.69% of cases, compared to bosentan and macitentan.

Key Points

The study aims to identify and compare adverse drug events associated with endothelin receptor antagonists using FAERS data.
Conducted disproportionality analysis of individual case safety reports from FAERS between Q1 2004 and Q2 2025.
Classified adverse drug events utilizing MedDRA terminology.
Executed signal detection using ROR, PRR, BCPNN, and MGPS algorithms.
Performed Time-to-Onset analysis to evaluate the timing of adverse drug events.
Collected 35,112, 48,411, and 29,877 adverse drug event reports for bosentan, ambrisentan, and macitentan, respectively.
Ambrisentan had the highest incidence of adverse drug events at 42.69% of reports.
Identified significant signals in hepatobiliary, hematologic, cardiovascular, respiratory, and fluid retention categories.
New adverse drug events included jaw pain, pulmonary thrombosis, gout, decreased blood potassium, and hypotension.
Most adverse drug events occurred within the first year of treatment.

Study Design

Type

Observational (n=113,400)

Multicenter

Yes

Structured PICO

Do endothelin receptor antagonists (bosentan, ambrisentan, macitentan) have distinct adverse drug event profiles and novel safety signals in real-world pharmacovigilance data?

Population

113,400 adverse event reports (35,112 for bosentan, 48,411 for ambrisentan, 29,877 for macitentan) from the FAERS database (Q1 2004 to Q2 2025), majority female (male-to-female ratio 1:2.91), aged between 18 and 65 years.

Intervention

Endothelin receptor antagonists (bosentan, ambrisentan, and macitentan)

Comparator

Full dataset comparator (all other drugs in the FAERS database)

Outcome

Disproportionate reporting signals of adverse drug events (ADEs) classified by MedDRA terminology, detected using ROR, PRR, BCPNN, and MGPS algorithmssafety

Real-world pharmacovigilance data confirms known adverse events of endothelin receptor antagonists and identifies novel signals such as jaw pain, pulmonary thrombosis, and hypokalemia, highlighting the need for comprehensive monitoring.

Limitations

Missing age data in ADE reports may affect demographic representation.
Not all case reports clearly establish causality between drug and adverse events.

Abstract

Background 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. Objective 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. Methods 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. Results 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. Conclusion 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.

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