The Impact of ERA Switching on Risk Stratification in Pulmonary Arterial Hypertension

Overview

Pulmonary arterial hypertension (PAH) is a rare, progressive, and potentially fatal disease characterized by increased pulmonary vascular resistance and right ventricular dysfunction. Among the four major molecular pathways involved in PAH pathophysiology-nitric oxide, prostacyclin, activin, and endothelin-1 (ET-1)-the endothelin pathway plays a central role. Endothelin-1 acts on ETA and ETB receptors, inducing vasoconstriction and vascular remodeling. Endothelin receptor antagonists (ERAs) are cornerstone therapies in PAH. Ambrisentan is selective for ETA and associated with a lower risk of hepatotoxicity. Bosentan, a dual ERA (ETA/ETB), has well-established efficacy but a higher incidence of liver enzyme elevation, with approximately 9% of patients experiencing hepatic side effects and about 2% discontinuing therapy due to hepatotoxicity. While transitions between ERAs occur in routine clinical practice, data on their clinical impact are scarce. This prospective, observational, single-center cohort study aims to evaluate the effect of switching from ambrisentan to bosentan on risk stratification using the COMPERA 2.0 and REVEAL Lite 2.0 scores at 3-6 months post-switch. Secondary outcomes include variations in functional class (WHO/NYHA), 6-minute walk distance (6MWD), NT-proBNP levels, incidence of adverse events (with a focus on hepatotoxicity), and hematologic parameters such as anemia. The study will enroll adult patients (≥18 years) with confirmed PAH by right heart catheterization who have undergone a documented switch from ambrisentan 10 mg to bosentan 125 mg within the last 6 months. The primary endpoint is the proportion of patients whose risk category changes post-transition according to COMPERA 2.0 and REVEAL Lite 2.0. The results are expected to provide clinically relevant insights into therapeutic decisions involving ERA transitions in PAH management.

Pulmonary arterial hypertension (PAH) is a progressive, life-threatening disease characterized by pulmonary vascular remodeling, increased pulmonary vascular resistance, and right ventricular failure. Among the key molecular pathways implicated in its pathogenesis, the endothelin system plays a central role. Endothelin-1 (ET-1) promotes vasoconstriction and proliferation primarily through ETA receptors, while ETB receptors help mediate ET-1 clearance and vasodilation. Endothelin receptor antagonists (ERAs) have become foundational in PAH therapy. Ambrisentan, a selective ETA receptor antagonist, is associated with favorable safety and convenience profiles, including once-daily dosing and lower hepatotoxicity risk. Bosentan, a dual ETA/ETB antagonist, is effective but necessitates regular liver function monitoring due to its known hepatic adverse effects. In clinical practice, transitioning between ERAs is not uncommon and may be driven by clinical response, side effect profiles, or drug availability. However, limited prospective data exist regarding the safety and clinical implications of switching from ambrisentan to bosentan. Most available evidence is derived from small retrospective cohorts, such as the study by Gong et al. (2022), which suggested that such a transition does not negatively impact hemodynamics, functional class, or exercise capacity. The ACTION study is a prospective observational cohort designed to systematically evaluate the real-world impact of this therapeutic transition. Specifically, it will assess whether switching from ambrisentan to bosentan influences validated multidimensional risk stratification tools-COMPERA 2.0 and REVEAL Lite 2.0-which integrate clinical, functional, and biochemical parameters to estimate prognosis in PAH patients. Eligible patients will be adults with confirmed PAH who transitioned therapies within the past six months. Baseline data collected at the time of the medication switch will be compared with follow-up data after 3-6 months of treatment with bosentan. By focusing on risk reclassification, the study aims to determine whether ERA switching introduces measurable clinical impact as captured by these scores. The study also seeks to capture data on tolerability and laboratory safety, especially related to hepatic enzymes and hematologic changes. Given the absence of randomized data in this area, the ACTION study may provide practical insights into treatment adaptation strategies in PAH, especially in resource-limited settings or when access to specific medications is restricted.