Riociguat replacement and selexipag add-on show no significant difference in pulmonary arterial hypertension outcomes

Pulmonary arterial hypertension (PAH) remains a severe condition despite existing therapies. Many patients exhibit inadequate responses to standard combination therapy, typically involving endothelin receptor antagonists (ERAs) and phosphodiesterase-5 inhibitors (PDE5is). This therapeutic gap necessitates further treatment options. Riociguat, a soluble guanylate cyclase (sGC) stimulator, and selexipag, a prostacyclin (IP) receptor agonist, are both approved as next-step therapies. However, direct head-to-head trials comparing their effectiveness and safety have been lacking, leaving clinicians without clear guidance on optimal sequencing or choice.

Researchers conducted a systematic review and indirect treatment comparison of riociguat replacement therapy and selexipag add-on therapy in PAH patients. They systematically searched PubMed, EMBASE, and Cochrane Library for randomized controlled trials (RCTs) involving either compound up to November 4, 2025. Three RCTs (REPLACE, GRIPHON main, and GRIPHON post-hoc, plus a phase II trial) were included. Study quality was assessed using Cochrane's Risk of Bias 2.0 tool. Indirect treatment comparisons were performed using Bucher's method within a common comparator framework of ERA + PDE5i baseline therapy.

The systematic review included three RCTs (four publications), with an overall low risk of bias, except for the phase II trial due to its small sample size. Indirect comparisons revealed no significant differences between riociguat and selexipag for any primary or secondary outcome. The hazard ratio for clinical worsening was 0.167 (95% CI: 0.0019-1.495, p = 0.1066), indicating no statistically significant difference. Mean differences for 6-min walk distance and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were 10.64 m (95% CI: -9.158 to 30.438, p = 0.2920) and -46.62 pg/mL (95% CI: -307.826 to 214.586, p = 0.7263), respectively, again showing no significant distinction.

The relative risk of overall adverse events was 1.07 (95% CI: 0.90-1.27, p = 0.453), confirming comparable safety profiles between the two treatments. Subgroup analyses, including patients on baseline ERA + PDE5i therapy, also yielded similar results.