CADENCE: Sotatercept Significantly Benefits Patients With CpcPH, HFpEF

The CADENCE study, presented at ACC.26 and simultaneously published in Circulation, shows that sotatercept, an activin signaling inhibitor, meaningfully improves pulmonary vascular and cardiac hemodynamics in patients with heart failure with preserved ejection fraction (HFpEF) and severe combined post‑ and precapillary pulmonary hypertension (CpcPH). 

In this phase 2, randomized trial, 164 patients (mean age 75, 70% women) on guideline‑directed HFpEF therapy were assigned to sotatercept 0.3 mg/kg, 0.7 mg/kg, or placebo every 3 weeks for 24 weeks.

At 24 weeks, the primary endpoint, pulmonary vascular resistance (PVR), dropped significantly with sotatercept versus placebo, with median changes of −0.67 and −0.33 Wood units in the lower‑ and higher‑dose groups versus +0.26 in placebo. 

Both sotatercept doses also reduced mean pulmonary artery pressure (mPAP) by about 9 mm Hg, pulmonary arterial wedge pressure (PAWP) by 2.5–3.0 mm Hg, and improved six‑minute walking distance, with a marked reduction in time to clinical worsening at the 0.3 mg/kg dose. 

Adverse events were modest, led mainly by increased hemoglobin and diarrhea, and were generally consistent with prior sotatercept trials.

The authors interpret the results as proof of concept that targeting activin signaling can improve both right‑ and left‑sided heart failure parameters—including left atrial pressure and volume—beyond modest PVR reductions. 

An editorial highlights that CADENCE shifts the focus from purely hemodynamic improvement to reversing fibrosis and cellular hypertrophy, marking an early step toward mechanism‑driven therapy for HFpEF‑associated pulmonary vascular disease. 

These findings support further development of sotatercept and similar ligand‑trap strategies in CpcPH and advanced HFpEF.