CADENCE Trial Signals Breakthrough in Heart Failure with Preserved Ejection Fraction and Pulmonary Hypertension

What was the primary clinical rationale for the CADENCE trial, and how does it address an unmet need in this population?

Sotatercept is approved for pulmonary arterial hypertension.^1-4 It has shown to not only dramatically improve pulmonary arterial pressure and pulmonary vascular resistance, but this translated into improvement in clinical outcomes across three pivotal phase 3 trials: STELLAR (A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Compare the Efficacy and Safety of Sotatercept Versus Placebo When Added to Background Pulmonary Arterial Hypertension (PAH) Therapy for the Treatment of PAH; ClinicalTrials.gov identifier: NCT04576988), ZENITH (A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Sotatercept When Added to Maximum Tolerated Background Therapy in Participants With Pulmonary Arterial Hypertension [PAH] World Health Organization [WHO] Functional Class [FC] III or FC IV at High Risk Mortality; ClinicalTrials.gov identifier: NCT04896008) and Hyperion (A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate Sotatercept When Added to Background Pulmonary Arterial Hypertension [PAH] Therapy in Newly Diagnosed Intermediate- and High-risk PAH Patients; ClinicalTrials.gov identifier: NCT04811092). HFpEF has many phenotypes. CADENCE (A Phase 2, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Effects of Sotatercept Versus Placebo for the Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension [Cpc-PH] Due to Heart Failure With Preserved Ejection Fraction [HFpEF]; ClinicalTrials.gov identifier: NCT04945460) focused on the RV/PA phenotype, one which has pulmonary venous hypertension from left heart disease that overtime causes pulmonary arterial remodeling.^5,6 Combined post and pre-capillary pulmonary hypertension is a condition of both pulmonary vascular disease and cardiac disease – HFpEF. These patients have a high morbidity and mortality. There are no currently approved targeted therapies.

What were the key elements of the CADENCE trial design, the inclusion/exclusion criteria and what were the primary and secondary endpoints?

Patients had to have CpcPH by right heart catheterization with pulmonary vascular resistance (PVR) >=4 wood units. This is higher than the defined number of >2 so that we could enrol the correct phenotype. Patients were symptomatic and on stable therapy for 30 days.

What do the CADENCE results tell us about the role of activin signaling modulation in pulmonary vascular remodelling in HFpEF-associated pulmonary hypertension?

The results demonstrated both direct pulmonary vasculature and cardiac benefits. CADENCE met its primary endpoint, a decrease in PVR for both the 0.7 and 0.3 mg/kg dosing groups shown here. Sotatercept use yielded a statistically significant, placebo-corrected decrease in PVR at 24 weeks of 0.75 Units in the 0.7mg/kg dose and 1.02 in the 0.3 mg/kg dose. Sotatercept treatment produced a significant reduction in right atrial pressure, mean pulmonary artery pressure and wedge pressure indicating lower right- and left-sided filling pressures.

Sotatercept treatment did not change oxygen delivery.

Based on this trial, how do you envision sotatercept potentially fitting into the therapeutic landscape for patients with HFpEF and pulmonary hypertension, and what do you think are the key questions the next phase of research needs to answer?

We need to do a phase 3 study, but this gives us hope that we can finally have a targeted therapy for this sick population. The study also had a small subset of patients post valvular repair; the numbers are small, but the drug was tolerated without safety signals. Potential expansion to other phenotypes of Group 2 pulmonary hypertension (PH) could then be evaluated. I hope this excites my colleagues so that we can have a fast enrolment for the next trial. It also has opened up discussion about how our antiproliferative agents affect the entire vasculature, as the studies now in PAH and CADENCE demonstrate an integrated cardiopulmonary system.

References

1. Humbert M, McLaughlin V, Gibbs JSR, et al. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2021;384:1204-15.
2. Hoeper MM, Badesch DB, Ardeschir G, et al. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2023;388:1478-90.
3. Humbert M, McLaughlin VV, Badesch DB, et al. Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death. N Engl J Med. 2025;392:1987-2000.
4. McLaughlin VV, Hoeper MM, Badesch DB, et al. Sotatercept for Pulmonary Arterial Hypertension within the First Year after Diagnosis. N Engl J Med. 2025;393:1599-1611.
5. Gomberg-Maitland M, Tedford RJ, Langleben D, et al. Sotatercept for Combined Post- and Pre-capillary Pulmonary Hypertension Associated With Heart Failure: Results from the Phase 2, Randomized, Placebo-Controlled CADENCE Study. Circulation. 2026; doi: 10.1161/CIRCULATIONAHA.126.079918
6. Gomberg-Maitland M. Efficacy and Safety of Sotatercept in Combined Post- and Pre-Capillary Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction: Results From the Phase 2 Cadence Trial. Presented at ACC 2026, New Orleans, LA, USA, 29 March 2026.

SIGN UP to touchCARDIOLOGY!

Register Register

Join our global community today for access to thousands of peer-reviewed articles, expert insights and learn-on-the-go education across 150+ specialties, plus concise email updates and newsletters so you never miss out.