Indirect Treatment Comparison of Riociguat Replacement Therapy and Selexipag Add-on Therapy in Patients With Pulmonary Arterial Hypertension: Results From a Systematic Review.

Background: Despite standard combination therapy with endothelin receptor antagonists (ERAs) and phosphodiesterase-5 inhibitors (PDE5is), many patients with pulmonary arterial hypertension (PAH) show inadequate therapeutic responses. Riociguat (a soluble guanylate cyclase stimulator) and selexipag (a prostacyclin receptor agonist) are both approved as next-step therapies; however, their comparative effectiveness and safety remain unknown due to the lack of head-to-head trials. We aimed to compare the therapeutic effects of riociguat replacement and selexipag add-on therapy through an indirect treatment comparison. Methods: Randomized controlled trials (RCTs) involving patients with PAH receiving either riociguat or selexipag were identified through a systematic search of PubMed, EMBASE, and the Cochrane Library up to 04 November 2025. This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Study quality was assessed with Cochrane's Risk of Bias 2.0 tool. Indirect treatment comparisons using Bucher's method were conducted within a common comparator (ERA + PDE5i) framework. Subgroup analyses of patients receiving baseline ERA + PDE5i therapy and those classified as World Health Organization functional class III also showed no significant differences. Conclusions: We found no significant differences between riociguat replacement and selexipag add-on therapy. These findings provide comparative data to help clinicians and patients make informed treatment decisions. Further head-to-head trials are needed to confirm comparative effectiveness. This review adhered to PRISMA 2020 guidelines. The PROSPERO Registration: CRD42024524391 https://www.crd.york.ac.uk/PROSPERO/view/CRD42024524391.