Background Sotatercept, an activin receptor ligand trap, has demonstrated significant short-term hemodynamic improvements in pulmonary hypertension (PH) based on clinical trials. However, evidence regarding long-term outcomes in real-world settings remains limited.

Methods Using data from the TriNetX global federated health research network covering 102 healthcare organizations, we conducted a retrospective cohort study comparing 185 patients with PH receiving sotatercept to 212,349 PH patients not receiving sotatercept. After 1:1 propensity score matching to balance baseline characteristics, we assessed outcomes at 6 months, 1 year, 3 years, and 5 years post-initiation and cox proportional hazards was used. Primary outcomes included all-cause mortality, rehospitalization rates, major adverse cardiovascular events (MACE), and BNP elevation (≥100 pg/mL).

Results Over 5 years of follow-up, sotatercept treatment was associated with significantly lower all-cause mortality (5.4% vs. 27.3%; risk difference, -21.9 percentage points [95% CI, -29.1 to -14.7]; p<0.001; hazard ratio [HR], 0.40 [95% CI, 0.16-0.99]). Rehospitalization rates were also substantially reduced in the sotatercept group (15.4% vs. 38.1%; risk difference, -22.8 percentage points [95% CI, - 35.8 to -9.7]; p=0.002; HR, 0.12 [95% CI, 0.03-0.49]). MACE occurrence was significantly lower with sotatercept (6.4% vs. 15.5%; risk difference, -9.1 percentage points [95% CI, -16.2 to -2.0]; p=0.011; HR, 0.45 [95% CI, 0.14-1.41]), while BNP elevation showed no significant difference (12.8% vs. 10.6%; p=0.626). Treatment benefits were observed as early as 6 months post-initiation, progressively increasing magnitude through 5 years of follow-up. Sensitivity analyses using alternative matching methods and instrumental variable approaches confirmed the robustness of these findings.

Conclusions In this large real-world cohort study with long-term follow-up, sotatercept was associated with substantial reductions in mortality, rehospitalization, and cardiovascular events in patients with pulmonary hypertension. These benefits increased over time, suggesting potential disease-modifying effects beyond acute hemodynamic improvements. These findings complement data from randomized controlled trials and support the role of sotatercept in improving long-term outcomes in pulmonary hypertension.

The authors have declared no competing interest.

This study did not receive any funding

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Financial Disclosures: None of the authors received any financial support

Conflict of Interest: None

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