Efficacy and safety of sotatercept in pulmonary arterial hypertension: A systematic review and meta-analysis of randomized controlled trials

BACKGROUND: Sotatercept, a first-in-class activin signaling inhibitor, represents a paradigm shift in pulmonary arterial hypertension (PAH) by directly targeting pulmonary vascular remodeling. We conducted a meta-analysis of randomized controlled trials (RCTs) to quantify its efficacy and safety. METHODS: We systematically searched PubMed, Embase, and Cochrane Central from inception to October 2025 for RCTs comparing sotatercept with placebo in PAH. The primary outcome was trial-defined clinical worsening (CW). Secondary outcomes included all-cause mortality, multicomponent improvement (MCI), attainment of low-risk status, serious adverse events (SAEs), and bleeding. Data were pooled using a Mantel-Haenszel random-effects model. Risk of bias was assessed with RoB 2.0, certainty of evidence using GRADE, and trial sequential analysis (TSA) was performed to assess conclusiveness. RESULTS: Four RCTs comprising 921 patients (sotatercept n = 483; placebo n = 438) were included. Sotatercept significantly reduced clinical worsening (OR 0.18, 95 % CI 0.12-0.27) with minimal heterogeneity and TSA-confirmed conclusiveness. All-cause mortality showed a favorable but non-significant trend (OR 0.63, 95 % CI 0.33-1.20). Sotatercept significantly increased MCI (OR 4.68, 95 % CI 1.94-11.31) and attainment of low-risk status (OR 2.77, 95 % CI 1.49-5.17), with moderate heterogeneity. SAEs were reduced (OR 0.72, 95 % CI 0.53-0.99), while bleeding risk was increased, predominantly minor mucocutaneous events (OR 2.84, 95 % CI 1.94-4.15). CONCLUSION: Sotatercept markedly reduces clinical worsening and improves multidimensional outcomes in PAH with an acceptable safety profile, supporting its role as a disease-modifying therapy.