Pulmonary Hypertension

CADENCE — Sotatercept for Combined Post- and Precapillary PH in HFpEF (Phase 2)

• Authors: CADENCE investigators
• Journal / date: Circulation, 2026
• DOI / URL: 10.1161/CIRCULATIONAHA.126.079918 | PMID 41904795
• Source basis: Abstract only
• Study type: Phase 2, multicenter, randomized, placebo-controlled
• PH group: 2 (Cpc-PH in the setting of HFpEF) — straddles HF and PH
• Population: N=164 adults with combined post- and precapillary PH in HFpEF, baseline median PVR 5.2 (IQR 4.0-6.9) Wood units
• Intervention / comparator: Sotatercept 0.3 mg/kg vs 0.7 mg/kg vs placebo SC every 3 weeks, 24 weeks
• Primary endpoint & result: Change in PVR at week 24.
• Hodges-Lehmann shift vs placebo: −1.02 WU (95% CI −1.81 to −0.23; p=0.004) for 0.3 mg/kg
• −0.75 WU (95% CI −1.52 to 0.03; p=0.024) for 0.7 mg/kg
• Key secondary endpoints:
• mPAP: ~−9 mmHg both doses vs placebo
• PAWP: ~−3 mmHg both doses vs placebo
• 6MWD: +20.3 m for 0.3 mg/kg, +5.8 m for 0.7 mg/kg
• Safety: Most common AEs — increased hemoglobin and diarrhea.
• Why it matters (clinical takeaway):
• First positive RCT in Cpc-PH-HFpEF, a population with NO proven therapies. This is a major signal — sotatercept lowered PVR, mPAP, and PAWP simultaneously with a directional improvement in 6MWD.
• The lower dose (0.3 mg/kg) outperformed the higher dose on PVR — supports starting low, watching for hemoglobin rise.
• Sets up a definitive Phase 3 outcomes trial. For now, this is proof-of-concept — not a guideline-level recommendation to treat.
• Caveats / limitations: Phase 2, 24-week hemodynamic endpoint. No hard outcomes (HF hospitalization, mortality) yet. Inverse dose-response on PVR is unexplained and needs replication.
• Trial registry: NCT04945460
• Referenced trials pulled forward: STELLAR (sotatercept in PAH Group 1) — to add to trials/ on next pass.