Clinical, hemodynamic, and safety outcomes of sotatercept in pulmonary arterial hypertension: a meta-analysis of randomized trials with time-to-event data.

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.