Background: This study assessed the efficacy and tolerability of the oral prostacyclin receptor agonist selexipag as part of sequential triple combination therapy in patients with pulmonary arterial hypertension (PAH).

Methods: The study retrospectively analyzed 127 of 1160 PAH patients from a single-center registry who received sequential triple therapy including selexipag. Clinical, echocardiographic, and hemodynamic variables and multiparametric risk scores (MRS) were evaluated to assess changes in risk and outcomes.

Results: The mean age was 43.2 ± 16.4 years, and 84.3% were female. Prior to selexipag initiation, Comparative Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension 2.0 risk strata were: 15% first, 31.5% second, 44.1% third, and 9.4% fourth; European Society of Cardiology/European Respiratory Society low-, intermediate-, and high-risk rates were 20.5%, 61.4%, and 18.1%, respectively. Mean REVEAL Lite 2.0 score was 6.3 ± 2.7. Maximal selexipag dosing reached 1600 μg BID in 18.1% of patients, while 64.6% remained at ≤1000 μg BID. Patients were grouped into low-, intermediate-, and high-dose cohorts. Median follow-up was 727.5 days (interquartile range (IQR) 224-985). Selexipag was discontinued in 15% of patients. Across dosing cohorts, initial improvements in functional class, 6-minute walk distance, right ventricular and pulmonary echocardiographic parameters, and MRSs during the first year attenuated thereafter, except for N-terminal pro-brain natriuretic peptide and Tricuspid annular plane systolic excursion/pulmonary arterial systolic pressure ratio. Lower baseline REVEAL Lite 2.0 score predicted low-risk status at final assessment (P = .017). Three-year survival was 72.5%, 85.7%, and 75.1% in low-, medium-, and high-dose cohorts (P > .05). Mortality was independently predicted by baseline Swedish PAH Registry, REVEAL 2.0, REVEAL Lite 2.0, and REVEAL Echo scores.

Conclusion: Earlier escalation to triple therapy with selexipag may improve outcomes. Baseline risk—but not achieved selexipag dose—was associated with survival. A possible decline in treatment effect after 1 year warrants further investigation.