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

Pulmonary arterial hypertension (PAH) is a progressive and potentially life-threatening condition characterized by pulmonary vascular remodeling, increased pulmonary vascular resistance, right ventricular dysfunction, and premature mortality. Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct form of precapillary pulmonary hypertension classified as World Health Organization Group 4. In selected patients with PAH or inoperable or residual CTEPH, therapies targeting the endothelin pathway may be used as part of clinical management. Endothelin-1 contributes to pulmonary vasoconstriction and vascular remodeling through ETA and ETB receptors. Endothelin receptor antagonists are an established component of PAH treatment. Ambrisentan selectively antagonizes the ETA receptor and is administered once daily, whereas bosentan is a dual ETA/ETB receptor antagonist that requires regular monitoring because of its potential hepatic and hematologic adverse effects. Transitions between medications within the ERA class may occur because of adverse events, clinical considerations, patient-related factors, or medication availability. However, evidence regarding the clinical consequences of switching from ambrisentan to bosentan is limited, particularly when the transition is imposed by an external disruption in medication supply rather than planned as an elective therapeutic strategy. The ACTION study is a retrospective, observational, single-center cohort study designed to assess the real-world clinical impact of switching from ambrisentan to bosentan. The study includes adults aged 18 years or older with PAH or CTEPH confirmed by right heart catheterization. Two exposure groups will be evaluated: patients who transitioned from ambrisentan 10 mg to bosentan 125 mg following a national shortage of ambrisentan and patients with a similar clinical profile who remained on ambrisentan. Baseline data will correspond to the clinical assessment performed at or near the time of the medication transition in the switch group and to a comparable reference assessment in the maintenance group. Follow-up data recorded 3 to 6 months later will be used to evaluate changes within each group and differences between groups. The primary outcome is worsening of risk stratification after the medication transition, comparing patients who switched to bosentan with patients who remained on ambrisentan. Risk will be assessed using COMPERA 2.0 and REVEAL Lite 2. Analyses will include between-group comparisons and within-group comparisons of risk categories and their individual components. Secondary outcomes include changes in World Health Organization/New York Heart Association functional class, 6-minute walk distance, BNP levels, hepatic transaminases, and hemoglobin. The study will also evaluate clinically relevant events, including hospitalization, emergency department visits, initiation of supplemental oxygen, and decompensation of right heart failure. By including a contemporaneous maintenance group, the ACTION study seeks to distinguish changes potentially associated with the medication switch from changes related to the natural course of pulmonary hypertension and routine clinical follow-up. The results may provide clinically relevant evidence regarding the safety and consequences of non-elective ERA substitution in real-world care.