Key result
Sotatercept cuts clinical worsening or death by ~77% versus control in PAH.
Why the study?
Pulmonary arterial hypertension remains progressive despite contemporary background therapy, and sotatercept may improve clinical and hemodynamic outcomes by targeting pulmonary vascular remodeling.
Does sotatercept added to background therapy reduce clinical worsening or death in patients with pulmonary arterial hypertension?
Meta-Analysis (n=889)
Does sotatercept added to background therapy reduce clinical worsening or death in patients with pulmonary arterial hypertension?
Hazard Ratio: 0.23 (95% CI 0.16–0.32)
p-value: p=<0.001
Sotatercept as an add-on therapy significantly reduces clinical worsening or death and improves hemodynamics and functional class in patients with PAH, though it increases the risk of bleeding events.
Supports sotatercept addition to PAH background therapy; confirms robust efficacy across RCTs while flagging bleeding risk.
Background: Pulmonary arterial hypertension (PAH) remains progressive despite contemporary background therapy. Sotatercept is a novel activin signaling inhibitor that targets pulmonary vascular remodeling and may improve clinical and hemodynamic outcomes. Objectives: To evaluate the efficacy, hemodynamic effects, and safety of sotatercept in patients with PAH. Design: Systematic review and meta-analysis of randomized controlled trials (RCTs). Data sources and methods: Five electronic databases were searched through October 2, 2025, for eligible RCTs. Time-to-event outcomes were analyzed using pooled individual patient data with hazard ratios (HRs), while secondary outcomes were assessed using random-effects risk ratios (RRs) and mean differences (MDs), with 95% confidence intervals (CI). Trial-sequential analysis (TSA) evaluated the conclusiveness of results. Results: In four RCTs ( n = 889), sotatercept reduced clinical worsening or death by 77% (HR 0.23, 95% CI 0.16–0.32, p < 0.001) and prolonged event-free survival by ~40 weeks. World Health Organization (WHO) functional class improved in 40.3% vs 24.3% (RR 1.71, 95% CI 1.32–2.21), and 6-minute walk distance increased by MD 30.27 m (95% CI 13.45–47.08), while pulmonary vascular resistance (PVR) declined significantly (MD −247 dyn·s·cm– 5 , 95% CI −301.7; −192.2). Serious adverse events were slightly less frequent with sotatercept (26.2% vs 31.7%, RR 0.83); however, total bleeding (37.9% vs 18.7%, RR 2.00), epistaxis (26.7% vs 5.4%, RR 4.89), and telangiectasia (19.8% vs 6.4%, RR 3.24) were more common. TSA revealed conclusiveness in clinical worsening, WHO functional class, and PVR, as well as increases in bleeding events and epistaxis. Conclusion: Sotatercept significantly improves clinical outcomes and extends event-free survival in PAH, with an acceptable safety profile; however, caution is warranted regarding bleeding events. These results support its role as an add-on therapy in PAH management. Trial registration: PROSPERO ID: CRD420251166414.
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Murad et al. (2026) conducted a meta-analysis in Pulmonary arterial hypertension (n=889). Sotatercept vs. control was evaluated on clinical worsening or death (HR 0.23, 95% CI 0.16-0.32, p=<0.001). Sotatercept significantly reduced clinical worsening or death by 77% (HR 0.23; 95% CI 0.16-0.32; p<0.001) compared to control in patients with pulmonary arterial hypertension.
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