An invited commentary examined a recent analysis of early selexipag addition to double therapy for pulmonary arterial hypertension.

The commentary, authored by John Granton, MD, and Gerry Coghlan, MD, and published in JAMA Network Open, evaluated the methodology and findings of a real-world data analysis conducted by Burger et al. The original analysis utilized data from the Komodo Health payer dataset, representing more than 150 private payers in the United States. It assessed the association of selexipag with morbid events in patients with pulmonary arterial hypertension (PAH) who were recently prescribed a phosphodiesterase type 5 (PDE5) inhibitor and an endothelin receptor antagonist (ERA).

Among the key points from the commentary were:

• The analysis identified 2,966 eligible patients, of whom 351 (11.8%) added oral selexipag to their treatment regimen.
• Early exposure to selexipag was associated with decreased risk of all-cause hospitalization, PAH-related hospitalization, and PAH-related disease progression (defined as initiation of parenteral therapies, PAH-related hospitalization, death, transplant, or septostomy).
• Earlier exposure to selexipag (within 6 months) showed greater benefit compared with addition after 12 months.
• Results remained stable across different sensitivity analyses regarding duration of exposure to baseline treatments with ERAs, PDE5 inhibitors, or both.

The commentary authors noted that the researchers employed inverse probability censoring weights to control for available covariates. Patients who experienced an event were replicated in both groups prior to initiating selexipag, using baseline data from all patients not treated with up-front selexipag.

Limitations highlighted:

• Clinical features used in PAH risk assessments were not available, including: functional capacity (walk distance and New York Heart Association classification), symptoms, and laboratory data (eg, N-terminal pro–B-type natriuretic peptide and echocardiogram data).
• Only 37% of patients in the cohort were registered as having dyspnea, the most common symptom in PAH.
• Only 36% of patients were recorded as having a cardiac catheterization in the 6 months prior to diagnosis, raising concerns about the accuracy of PAH diagnoses in the cohort.
• Sociodemographic factors that may have influenced time to clinical worsening were not accounted for.

The commentary authors noted that the study cohort represented an older group of patients with a higher number of comorbidities compared with those in pivotal selexipag trials. Patients receiving double combination therapy had a mean of 3.13 comorbid conditions, with an identical frequency observed in patients given triple therapy.

The commentators provided context from previous research on selexipag in PAH treatment:

• The GRIPHON trial demonstrated a 40% reduction in morbidity and mortality events over a mean of 14 months with selexipag use.
• The TRITON trial found no therapeutic value when selexipag was used as part of an up-front triple therapy with an ERA and a PDE5 inhibitor.
• A 2023 post hoc pooled analysis of incident PAH patients from GRIPHON and TRITON trials showed a reduction in the risk of disease progression with selexipag (hazard ratio = 0.48; 95% confidence interval = 0.3–0.56).

The commentary highlighted that despite guideline recommendations, selexipag was not routinely prescribed and was more frequently discontinued compared with other PAH therapies. Challenges included a more difficult adverse effect profile, higher rates of intolerance, and the requirement for dose escalation.

While the analysis provided real-world evidence on the potential benefits of early selexipag addition in PAH treatment, the commentary authors emphasized that the limitations in available clinical data underscored the need for careful interpretation of the results in clinical practice.

Conflict of interest disclosures can be found in the commentary.