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

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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. Results: Three RCTs (four publications) were included: REPLACE, GRIPHON (main and post-hoc analyses), and a phase II trial. The overall risk of bias was low, except for the phase II trial, which had unclear risk due to its small sample size. Indirect comparisons showed no significant differences between the therapies for any outcome. The hazard ratio for clinical worsening was 0.167 (95% confidence interval [CI]: 0.0019–1.495, p = 0.1066). Mean differences for 6-min walk distance and N-terminal pro–B-type natriuretic peptide 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). The relative risk of overall adverse events was 1.07 (95% CI: 0.90–1.27, p = 0.453). 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.

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