RecentRCT

ZENITH

Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death

N Engl J Med, 2025 · Phase 3 multicenter double-blind randomized placebo-controlled trial (n=172), stopped early after a prespecified interim efficacy analysis

Clinical question

Does add-on sotatercept reduce major morbidity/mortality events in high-risk PAH despite maximum tolerated background therapy?

Population: Adults with high-risk pulmonary arterial hypertension receiving maximum tolerated background therapy
Intervention: Sotatercept added to background therapy
Comparator: Placebo added to background therapy
Primary outcome: Time to first death from any cause, lung transplantation, or hospitalization >=24 h for worsening PAH
Result: A primary endpoint event occurred in 17.4% with sotatercept versus 54.7% with placebo (HR 0.24; 95% CI 0.13 to 0.43; P<0.001). (HR 0.24 (95% CI 0.13-0.43), P<0.001)

What the trial found

Among high-risk PAH patients on maximum tolerated background therapy, sotatercept substantially reduced the composite of death, lung transplantation or PAH-worsening hospitalization.

Current guideline position

Integrate with current PAH specialty guidance and regulatory labeling; this does not replace ICU management of acute decompensated RV failure or transplant/MCS evaluation when indicated.

Clinical interpretation

Supports escalation with sotatercept in high-risk PAH under specialty care, while the early stopping and composite endpoint require outcome-specific interpretation.

Limitations

Stopped early at a prespecified interim analysis
Composite endpoint; individual component estimates are less precise than the overall treatment effect

Clinical Context & Relevant Topics (1)

Disease Reference

Pulmonary Hypertension & Acute Decompensation

Hemodynamic classification, right ventricular afterload reduction, selective pulmonary vasodilation, and pulmonary hypertensive crisis management.

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