Efficacy and Safety of Sotatercept in Pulmonary Arterial Hypertension: A GRADE-Assessed Meta-Analysis of Randomized Trials with Trial Sequential Analysis

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance. Sotatercept, an activin-signaling inhibitor, is a novel therapy targeting this pathology. We conducted a systematic review and meta-analysis to assess its efficacy and safety in PAH. A systematic search of PubMed, Cochrane CENTRAL, Scopus, and Web of Science was conducted, to identify randomized controlled trials (RCTs) evaluating Sotatercept in adults with PAH. Data were pooled using random-effects models to estimate mean differences (MDs) and risk ratios (RRs) with 95% confidence intervals (CIs). Four RCTs enrolling 921 patients were included. Compared with placebo, Sotatercept significantly improved 6-minute walk distance (MD 30.54 m, 95% CI 4.05–57.04, P=0.02), WHO functional class (RR 1.71, 95% CI 1.37–2.15, P<0.00001), multicomponent improvement (RR 2.77, 95% CI 1.45–5.29, P=0.002), pulmonary vascular resistance (MD −197.01 dyn⋅s⋅cm ⁻⁵ , 95% CI −213.16 – −180.86, P<0.00001), and reduced clinical worsening events (RR 0.28, 95% CI 0.21–0.38, P<0.00001). There were no significant differences in NT-proBNP levels or all-cause mortality. Safety analysis showed lower risks of serious adverse events (AEs), peripheral edema, and right ventricular failure, but higher rates of bleeding, epistaxis, and drug-related AEs. Sotatercept demonstrated meaningful clinical benefits in exercise capacity, hemodynamics, and disease progression among patients with PAH, with a generally acceptable safety profile. These findings support Sotatercept as a promising adjunct to standard therapy, though longer-term trials are needed to confirm durability and survival impact.