Pulmonary arterial hypertension outcomes better with early therapy augmentation with selexipag

In the treatment of patients with pulmonary arterial hypertension (PAH), adding selexipag as a third medication sooner rather than later is crucial to help prevent hospitalization and disease progression, as suggested in an emulated target trial.

Analysis of data from 2,966 patients (mean age 54.3 years, 71.6 percent female) with PAH showed that adding selexipag within 6 months of ongoing double oral therapy (DOT) consisting of an endothelin receptor antagonist (ERA) and a phosphodiesterase type 5 inhibitor (PDE5i) conferred an 18-percent reduction in the risk of all-cause hospitalization (adjusted hazard ratio [aHR], 0.82, 95 percent confidence interval [CI], 0.72–0.94) as compared with DOT alone. [JAMA Netw Open 2024;7:e2434691]

Similar reductions were observed in the risks of PAH-related hospitalization (aHR, 0.81, 95 percent CI, 0.70–0.95) and PAH-related progression (aHR, 0.82, 95 percent CI, 0.70–0.95).

“The greatest risk reduction across all outcomes was observed for escalation to triple oral therapy within 3 months,” the investigators noted.

More importantly, when a gap of 45 days instead of 90 days between medication refills was allowed, the magnitude of the observed risk reductions was even greater if oral selexipag was started within 3 months of DOT initiation. This was true for PAH-related hospitalization (45-day gap: aHR, 0.75, 95 percent CI, 0.61–0.92; 90-day gap: aHR, 0.85, 95 percent CI, 0.63–1.16) and PAH-related progression (45-day gap: aHR, 0.74, 95 percent CI, 0.61–0.90; 90-day gap: aHR, 0.88, 95 percent CI, 0.64–1.21).

Meanwhile, the beneficial effect of escalating to triple oral therapy disappeared if selexipag was initiated within 12 months.

“Understanding long-term healthcare use and clinical outcomes, such as hospitalization, under various therapies is central for improving the lives of patients with PAH given that hospitalizations among these patients are common, costly, and highly predicative of mortality risk,” the investigators pointed out. [Chest 2014;146:1263-1273; Am J Manag Care 2015;21:s47-s58; Chest 2019;156:323-337; J Am Coll Cardiol 2018;71:752-763]

“[The study] results reinforce the potential benefit of early up-front triple therapy of selexipag, macitentan, and tadalafil vs double therapy of macitentan, tadalafil, and placebo in preventing PAH-related progression found in the exploratory TRITON study,” they added. [J Am Coll Cardiol 2021;78:1393-1403]

The investigators stressed that prolonged treatment gaps, potentially due to challenges in adverse event management, may lead to poorer clinical outcomes in PAH. This, they added, is consistent with the general principle that consistently taking medication as prescribed is important for managing chronic diseases. [Oman Med J 2011;26:155-159; Br J Clin Pharmacol 2012;73:691-705]

For the study, data were obtained from the US Komodo claims database to emulate a randomized trial. Adult patients with PAH treated with ERA plus PDE5i were duplicated to triple oral therapy and DOT and artificially censored when observed treatment deviated from assigned treatment. Inverse probability of treatment weighting was applied to emulate hypothetical randomization, while censoring-induced selection bias was used to account for censoring-induced selection bias.

In the cohort, the most common PDE5i–ERA combination used was tadalafil–ambrisentan (32.7 percent), followed by sildenafil–ambrisentan (24.1 percent), sildenafil–macitentan (23.8 percent), and tadalafil-macitentan (15.5 percent). Most patients (69.4 percent) had systemic hypertension, and 24.2 percent had connective tissue disease.