Early Addition of Selexipag to Double Therapy for Pulmonary Arterial Hypertension

Abstract

Importance: A subgroup analysis of a randomized clinical trial established the efficacy of selexipag plus background therapy (monotherapy or double oral therapy [DOT]) vs placebo plus background therapy and found that the addition of selexipag within 6 months had an added benefit. However, the timing of selexipag addition to DOT and the incremental benefit in clinical practice is not well studied.

Objective: To compare triple oral therapy (TOT) consisting of selexipag, endothelin receptor antagonist (ERA), and phosphodiesterase type 5 inhibitor (PDE5i) vs DOT consisting of ERA and PDE5i.

Design, setting, and participants: This comparative effectiveness study was conducted using data from the US Komodo claims database to emulate a randomized trial. Patients aged 18 years or older with pulmonary arterial hypertension (PAH) treated with ERA plus PDE5i with records from July 2015 through June 2022 were duplicated to TOT and DOT and artificially censored when observed treatment deviated from assigned treatment. Hypothetical randomization was emulated using inverse probability of treatment weighting, and the study accounted for censoring-induced selection bias using inverse probability of censoring weighting. A pooled logistic model estimated the per-protocol difference between treatment groups. Data were analyzed from November 2022 through July 2023.

Interventions: TOT (addition of selexipag within 3, 6, and 12 months of initiating DOT) vs DOT.

Main outcomes and measures: Adjusted risk of all-cause hospitalization, PAH-related hospitalization, and PAH-related disease progression over a 2-year follow-up.

Results: A total of 2966 patients with PAH (mean [SD] age, 54.3 [14.0] years; 2125 female [71.6%]) met eligibility criteria. Adding selexipag within 6 months of ongoing DOT was associated with a reduction in risk for all-cause hospitalization (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.72-0.94), PAH-related hospitalization (aHR, 0.81; 95% CI, 0.70-0.95), and PAH-related progression (aHR, 0.82; 95% CI, 0.70-0.95) vs DOT alone. There were no associations if selexipag was initiated within 12 months for all-cause hospitalization, PAH-related hospitalization, or PAH-related disease progression. The association remained with a greater decrease in risk for disease progression vs DOT for selexipag initiation within 3 months (aHR, 0.74; 95% CI, 0.61-0.90).

Conclusions and relevance: This study found that early selexipag addition to ERA plus PDE5i was associated with a reduction in risk of hospitalization and disease progression. These findings suggest that delays in selexipag initiation likely contribute to suboptimal patient and health system outcomes.

Figure 1.. Examples of Cohort Assignment and Follow-Up Determination Under Target Trial Design

Patient types 1 to 4 are shown. DOT indicates double oral therapy; ERA, endothelin receptor antagonist; PDE5i, phosphodiesterase type 5 inhibitor; TOT, triple oral therapy.

Figure 2.. Adjusted Survival Curves by Strategy With 90-d Gap

DOT indicates double oral therapy; PAH, pulmonary arterial hypertension; TOT, triple oral therapy.

Figure 3.. Adjusted Survival Curves by Strategy With 45-d Gap

DOT indicates double oral therapy; PAH, pulmonary arterial hypertension; TOT, triple oral therapy.