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CADENCEHeart FailureCirculation
Sotatercept Improves Hemodynamics in Pulmonary Hypertension Associated With Heart Failure
Sotatercept for Combined Post- and Pre-capillary Pulmonary Hypertension Associated With Heart Failure: Results from the Phase 2, Randomized, Placebo-Controlled CADENCE Study
View Full PaperWhy the trial?
The CADENCE trial was conducted to address the lack of proven therapies for combined post- and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction (CpcPH–HFpEF), a condition involving remodeling of both the heart and pulmonary vasculature and associated with significant mortality.
Does sotatercept improve pulmonary vascular resistance in adults with combined post- and pre-capillary pulmonary hypertension associated with heart failure with preserved ejection fraction?
Key result
Sotatercept at 0.3 mg/kg and 0.7 mg/kg reduced pulmonary vascular resistance compared to placebo (shift -1.02 Wood units, P=0.004; and -0.75 Wood units, P=0.024, respectively) in CpcPH-HFpEF.
Authors
Discussion
Key questions
Member takes
Where experts stand
Experts read CADENCE as strong proof-of-concept for sotatercept in CpcPH-HFpEF, with enthusiasm centered on benefits beyond hemodynamics, and broad agreement that the data justify moving to a phase 3 trial.
Clinicians and the sponsor view CADENCE as a meaningful signal that sotatercept can improve both the pulmonary vasculature and cardiac function in a population with no approved therapy. The reaction is uniformly positive, with experts highlighting that the drug's effects go beyond simple hemodynamic improvement to target underlying disease biology. The live question is whether these phase 2 findings will hold up in a registrational phase 3 trial powered for clinical outcomes.
Agreement
Multiple experts emphasize that sotatercept's benefits in CADENCE extend beyond pulmonary vascular resistance reduction to include improvements in cardiac function, biomarkers, and clinical markers on both sides of the heart, suggesting the drug targets underlying biology rather than hemodynamics alone.
3 clinicians say this directly
Still unclear
Whether the 0.3 mg/kg dose truly optimizes the benefit-risk profile over the 0.7 mg/kg dose, and what clinical outcome endpoints a phase 3 trial should prioritize in this older, comorbid population. It also remains to be seen whether the hemodynamic and biomarker gains translate to durable improvements in hard clinical outcomes at scale.
Key expert perspectives
SSSatyam SarmaCardiologist, UT Southwestern Medical CenterContextMar 31
Sotatercept's value lies in targeting inflammation and cell proliferation, not just resting PVR
Sarma argues that the benefits transcend modest reductions in resting PVR and highlight the importance of targeting inflammation, cell proliferation, and endothelial function in HFpEF. He frames sotatercept as the first step in leveraging signaling networks to reverse fibrosis and cellular hypertrophy, and says CADENCE underscores that targeting underlying biologic mechanisms matters more than focusing solely on hemodynamic parameters.
Distilled from their postOriginal post
MGMardi Gomberg-MaitlandDirector, Pulmonary Hypertension Program, George Washington UniversityResults readoutMar 31
Improvements on both the right and left sides of the heart make this a big deal
Gomberg-Maitland highlights that sotatercept improved heart failure clinical markers and biomarkers on both right and left sides, including left atrial volume and wedge pressure. She notes that CpcPH-HFpEF has no approved treatments and high morbidity and mortality, and calls the data strong proof-of-concept supporting further evaluation in a phase 3 study.
RTRyan TedfordCardiologist, CADENCE trial investigatorResults readoutMar 31
PVR reduction translated into improved RV function and prolonged time to clinical worsening
Tedford reports that the PVR reduction was even more pronounced after adjusting for hemoglobin changes and translated into improved right ventricular function measured by TAPSE-to-PASP ratio. He notes improvements in natriuretic peptides, 6-minute walk distance, New York Heart Association class, and prolonged time to clinical worsening.
Distilled from their postOriginal post
Overview
Opens new treatment axis for CpcPH-HFpEF with none approved; extends sotatercept efficacy from PAH to this phenotype.
Key Points
- This research aimed to evaluate the efficacy of sotatercept in improving pulmonary vascular resistance in patients with combined post- and pre-capillary pulmonary hypertension associated with heart failure.
- Multicenter, randomized, placebo-controlled trial
- Adults received sotatercept (0.3 or 0.7 mg/kg) or placebo every 3 weeks
- Primary endpoint assessed pulmonary vascular resistance changes at week 24.
- The 0.3 mg/kg sotatercept group showed a median change of -0.67 Wood units (95% CI, -1.81 to -0.23; P=0.004) in pulmonary vascular resistance
- The 0.7 mg/kg sotatercept group showed a median change of -0.33 Wood units (95% CI, -1.52 to 0.03; P=0.024)
- Both doses observed reductions in mean pulmonary arterial pressure and pulmonary wedge pressure, with common adverse events including increased hemoglobin and diarrhea.
Study Design
Type
RCT (n=164)
Randomization
54:55:55
Multicenter
Yes
Structured PICO
Does sotatercept improve pulmonary vascular resistance in adults with combined post- and pre-capillary pulmonary hypertension associated with heart failure with preserved ejection fraction?
P
Population
164 adults with combined post- and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction (CpcPH-HFpEF)
I
Intervention
Sotatercept (0.3 or 0.7 mg/kg) every 3 weeks
C
Comparator
Placebo every 3 weeks
O
Outcome
Change in pulmonary vascular resistance at week 24surrogate
Sotatercept significantly reduced pulmonary vascular resistance at 24 weeks in patients with combined post- and pre-capillary pulmonary hypertension associated with HFpEF, providing proof of concept for activin signaling inhibition in this population.
Main Result
Effect estimate: Hodges-Lehmann shift -1.02 Wood units (95% CI -1.81 to -0.23)
Absolute Event Rate: -0.67% vs 0.26%
p-value: p=0.004
Coverage & sources
Journal, society, and media accounts. Useful signal, not independent expert judgment.
Cite This Study
Gomberg-Maitland et al. (2026) conducted an RCT in Combined post- and pre-capillary pulmonary hypertension associated with heart failure with preserved ejection fraction (CpcPH-HFpEF) (n=164). Sotatercept vs. Placebo was evaluated on change in pulmonary vascular resistance at week 24 (Hodges-Lehmann shift -1.02 Wood units, 95% CI -1.81 to -0.23, p=0.004). Sotatercept at 0.3 mg/kg and 0.7 mg/kg reduced pulmonary vascular resistance compared to placebo (shift -1.02 Wood units, P=0.004; and -0.75 Wood units, P=0.024, respectively) in CpcPH-HFpEF.