Efficacy and safety of sotatercept in pulmonary arterial hypertension: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remodeling and high mortality. Sotatercept, a novel activin signaling inhibitor, targets the underlying vascular pathology and offers therapeutic potential beyond current vasodilator-based therapies. A comprehensive search of PubMed, Web of Science, SCOPUS, and the Cochrane Library was performed up to April 2, 2025. Only randomized controlled trials (RCTs) comparing sotatercept to placebo in adults with PAH were included. Outcomes were pooled using random-effects models and reported as mean differences (MD) or risk ratios (RR) with 95% confidence intervals (CI). Trial sequential analysis (TSA) was conducted for statistically significant outcomes. PROSPERO ID: CRD420251031657. Three RCTs and 601 patients were included. Sotatercept significantly improved 6-min walk distance (MD = 40.17 m; 95% CI 15.14-65.19), decreased NT-proBNP (MD = - 1149.48 pg/mL; 95% CI - 1890.21 to - 458.73), improved WHO functional class (RR = 2.04; 95% CI 1.53-2.70), and decreased pulmonary vascular resistance (MD = - 214.58; 95% CI - 217.54 to - 211.62). Also, sotatercept decreased all-cause mortality (RR = 0.46; 95% CI 0.22-0.98) and right ventricular failure (RR = 0.26; 95% CI 0.09-0.75); however, it increased thrombocytopenia risk (RR = 2.01; 95% CI 1.01-3.98). Sotatercept significantly improves exercise capacity, cardiac biomarkers, functional status, and pulmonary hemodynamics in patients with PAH while reducing all-cause mortality and right ventricular failure. Despite a mild increase in the risk of thrombocytopenia, it remains a promising disease-modifying therapy.