OBJECTIVES: For patients with pulmonary arterial hypertension (PAH), selexipag is often added several months from initiating double oral therapy (DOT) with an endothelin receptor antagonist (ERA) and phosphodiesterase type 5 inhibitor (PDE5i). To appropriately assess the effectiveness of escalation to triple oral therapy (TOT) compared with DOT, it is critical to account for the DOT duration prior to selexipag initiation. This study compared the effectiveness of adding selexipag within 3, 6, and 12 months to DOT versus DOT alone for risk of hospitalization and PAH-related disease progression using a target trial design.

METHODS: A hypothetical, pragmatic trial protocol was developed to analyze real-world claims data from Komodo. Eligible study patients with PAH on DOT for 60 days between July 2015–June 2022 were cloned to both treatment groups and artificially censored when their observed treatment deviated from their assigned treatment strategy. Randomization was emulated using inverse probability treatment weight, and censoring-induced selection bias was accounted for using inverse probability censoring weight. A pooled logistic model was used to estimate the per-protocol effect between the treatment arms. Time to all-cause hospitalization, PAH-related hospitalization, and PAH-related disease progression were compared via adjusted hazard ratios (aHRs).

RESULTS: The risk of all-cause hospitalization (aHR=0.82;95%CI:0.72–0.94), PAH-related hospitalization (aHR=0.81;95%CI:0.70–0.95), and PAH-related disease progression (aHR=0.82;95%CI:0.70–0.95) were significantly lower among patients who added selexipag within 6 months of DOT compared with DOT alone. More pronounced treatment effects were observed when patients added oral selexipag early (3-months), or when continuous treatment was defined using a shorter gap in treatment (45 versus 90-days).

CONCLUSIONS: Adding selexipag as early as 3 months from initiation of DOT of ERA and PDE5i significantly reduced the risk of hospitalization among patients with PAH. Delays in selexipag initiation (≥12 months) and treatment gaps may contribute to suboptimal outcomes.