CADENCE
Sotatercept in Combined Post- and Precapillary Pulmonary Hypertension With Heart Failure and Preserved Ejection Fraction
Presented by Mardi Gomberg-Maitland — George Washington University
Subspecialty: Heart Failure
Published in Circulation
Key Result
Sotatercept significantly reduced pulmonary vascular resistance in HFpEF with CpcPH (0.3 mg/kg: -0.67 Wood units, p=0.004; 0.7 mg/kg: -0.33, p=0.024 vs +0.26 placebo). Time to clinical worsening reduced 82%.
What did this trial find?
The CADENCE phase 2 trial demonstrated that sotatercept significantly reduced pulmonary vascular resistance in patients with HFpEF and combined post- and precapillary pulmonary hypertension (CpcPH), meeting its primary endpoint. Both dose arms showed improvements across hemodynamic, functional, and clinical endpoints, with the 0.3 mg/kg dose showing an 82% reduction in time to clinical worsening. Coverage is largely positive and straightforward, with an accompanying Circulation editorial highlighting the importance of targeting underlying biology rather than just hemodynamics, and Merck announcing plans to advance to Phase 3.
Why does this trial matter?
Mostly straightforward positive coverage. The trial met its primary endpoint and all commentators are supportive. The accompanying editorial adds mechanistic framing but no real controversy. There is no meaningful pushback or critical counterpoint in available sources — the main nuances are the Phase 2 nature, the unexpected finding that the lower dose outperformed the higher dose on some endpoints, and the hierarchical testing limitation on some secondary endpoints. Quote supply is adequate but dominated by author and sponsor statements.
Study Design
Phase 2, randomized, double-blind, placebo-controlled trial (N=164)
Clinical Implications
Sotatercept shows promise as a disease-modifying therapy for the challenging HFpEF-CpcPH phenotype, an area with limited treatment options. Phase 3 trials are warranted.
Abstract
The CADENCE phase 2 trial evaluated sotatercept, an activin signaling inhibitor, in 164 patients (mean age 75, 70% women) with HFpEF and severe combined post- and precapillary pulmonary hypertension (CpcPH). Patients were randomized to sotatercept 0.3 mg/kg (n=54), 0.7 mg/kg (n=55), or placebo (n=55) every 3 weeks. At 24 weeks, the primary endpoint of pulmonary vascular resistance (PVR) was significantly reduced: -0.67 Wood units with 0.3 mg/kg (p=0.004) and -0.33 with 0.7 mg/kg (p=0.024), vs +0.26 with placebo. Both groups showed improvements in mean PAP (-9.2 mmHg), PAWP (-2.5 to -3.0 mmHg), and 6MWD (+5.8 to +20.3m). Time to clinical worsening was 82% lower in the 0.3 mg/kg group.