Abstract Rationale Pulmonary arterial hypertension (PAH) is a progressive disorder marked by elevated pulmonary vascular resistance (PVR), leading to right heart failure and reduced survival. The novel agent sotatercept, an activin signaling inhibitor, has emerged as an add-on therapy targeting vascular remodeling and pulmonary hemodynamics. This meta-analysis aimed to evaluate the clinical efficacy and safety of sotatercept compared with placebo in adults with PAH. Methods A systematic review and meta-analysis were conducted according to PRISMA guidelines. Electronic databases (PubMed, Scopus, Web of Science, Cochrane CENTRAL) were searched through October 2025 for randomized controlled trials comparing sotatercept versus placebo in adults with PAH receiving background therapy. The primary outcomes were changes in 6-minute walk distance (6MWD) and WHO functional class. Secondary outcomes included hemodynamic parameters (notably pulmonary vascular resistance PVR, mean pulmonary artery pressure, and cardiac output) and major adverse events (serious adverse events, bleeding, hypertension, and telangiectasia). Mortality data were extracted but interpreted cautiously due to limited follow-up and the add-on nature of sotatercept therapy. Random-effects models were applied, and publication bias was evaluated using funnel plots for functional and hemodynamic outcomes. The protocol was registered in PROSPERO (CRD420251184664). Results Four RCTs (ZENITH 2025, PULSAR 2021, STELLAR 2023, HYPERION 2025) comprising 921 participants were analyzed. The mean age ranged from 47.6-57.3 years; 75-80% were female and 85-90% White. Most patients had idiopathic or connective tissue disease-associated PAH (WHO functional class II-III) and were on combination therapy. Sotatercept significantly improved 6MWD (SMD = 7.14; 95% CI 1.11-13.17; p = 0.02; I² = 99.6%) and WHO functional class (OR = 2.39; 95% CI 1.76-3.23; p 0.0001; I² = 0%). Although PVR showed a reduction trend (SMD = −2.63; 95% CI − 5.83-0.57; p = 0.11; I² = 98.9%), results were heterogeneous. The pooled estimate for major adverse events favored sotatercept, with fewer serious events compared to placebo (OR = 0.69; 95% CI 0.49-0.99; p = 0.045). Mortality data were limited and not powered for statistical inference. Conclusion Sotatercept demonstrates significant functional and clinical benefits, improving exercise capacity and WHO functional class, with a favorable safety profile and reduction in major adverse events. While preliminary mortality and hemodynamic results suggest potential benefit, larger long-term trials are required to confirm sotatercept’s impact on survival and vascular remodeling in PAH. This abstract is funded by: None
Hasson et al. (Fri,) studied this question.