Hemodynamic effects of add-on therapies in pulmonary arterial hypertension: an additive component network meta-analysis

Abstract Background/Introduction Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance (PVR), leading to right heart failure and high mortality rates. Current treatments include endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors (PDE5i), soluble guanylyl cyclase stimulators (sGC-S), and prostanoids. Despite these therapies, prognosis remains poor, particularly for high-risk patients. Purpose We aimed to systematically analyze the hemodynamic effects of add-on PAH-medical treatments. Methods PubMed, CENTRAL and Web of Science was perused for randomized controlled trials (RCTs) assessing add-on PAH-drugs in patients on background treatment. An additive component network meta-analysis was performed for hemodynamic parameters (pulmonary vascular resistance PVR, mean pulmonary artery pressure mPAP, cardiac index CI). Results Out of 1,974 identified studies, 12 RCTs (1,312 patients with baseline and follow-up right heart catheterization) met inclusion criteria. Most patients were WHO functional class II or III, with a baseline 6MWD of 375±85 meters. The effect of add-on therapies on PVR was -3.2 WU for ERA, -2.9 WU for sotatercept, -2.3 WU for riociguat, -2.1 WU for oral prostanoids, -2.0 WU for PDE5i, -1.2 WU for seralutinib, and -0.3 WU for inhaled prostanoids. The highest PVR reduction was observed for the triple combination of ERA, PDE5i, and sotatercept with -8.1 WU (-10.2; -5.9). Add-on sotatercept led to the most significant reduction in mPAP (-12.1 mmHg), demonstrating superior efficacy compared to other therapies such as ERA (-5.5 mmHg) and sGC-S (-3.5 mmHg). Sotatercept monotherapy showed greater efficacy than PDE5i and oral prostanoids (p=0.035), and when combined with either ERA or PDE5i, outperformed triple therapy with oral prostanoids (p=0.035) and dual therapy with sGC-S (p=0.01), respectively. Cardiac index improvements were most pronounced with ERA (+0.6 L/min/m²), whereas sotatercept and seralutinib did not significantly affect CI. The additivity assumption was met (p=0.34), and no publication bias was detected, though moderate-to-high heterogeneity was observed. Conclusion(s) Add-on therapies for PAH considerably improve hemodynamics. Sotatercept emerges as a particularly promising option offering a potential non-invasive alternative to parenteral prostanoids. Further research should validate its role as an initial PAH treatment strategy.