CADENCE: sotatercept verlaagt pulmonale vaatweerstand bij gecombineerde pre/postcapillaire PH bij HFpEF

BACKGROUND: Combined post- and pre-capillary pulmonary hypertension in heart failure with preserved ejection fraction (CpcPH-HFpEF) involves remodeling in both the heart and pulmonary vasculature. Despite significant mortality, there are no proven therapies. METHODS: In this multicenter, randomized, placebo-controlled, phase 2 trial, adults received sotatercept (0.3 or 0.7 mg/kg) or placebo every 3 weeks. The primary end point was change in pulmonary vascular resistance at week 24. Hodges-Lehmann shift estimates described placebo-adjusted changes. RESULTS: 164 patients were randomized 54:55:55 to sotatercept 0.3 mg/kg, 0.7 mg/kg, and placebo (mean age 75, 70% women). Baseline median pulmonary vascular resistance was 5.2 (IQR 4.0–6.9) Wood units. The Hodges-Lehmann shift in pulmonary vascular resistance was −1.02 Wood units (95% CI −1.81 to −0.23; P=0.004) for 0.3 mg/kg and −0.75 (95% CI −1.52 to 0.03; P=0.024) for 0.7 mg/kg sotatercept. Mean pulmonary arterial pressure dropped by ~9 mmHg in both sotatercept groups, with reductions in pulmonary arterial wedge pressure of 3 and 2.5 mmHg. 6-minute walk distance improved 20.3 m at 0.3 mg/kg (95% CI 1.5–39.1) and 5.8 m at 0.7 mg/kg. Most common adverse events were increased haemoglobin and diarrhea. CONCLUSIONS: These findings provide proof of concept for improved pulmonary vascular and cardiac hemodynamics following activin signalling inhibition with sotatercept in patients with CpcPH-HFpEF. The 0.3 mg/kg dose had the most attractive efficacy-safety profile for phase 3 development.