Gomberg-Maitland Mardi, Badesch David B, Gibbs J Simon R, Grünig Ekkehard, Hoeper Marius M, Humbert Marc, Kopeć Grzegorz, McLaughlin Vallerie V, Meyer Gisela, Olsson Karen M, Preston Ioana R, Rosenkranz Stephan, Souza Rogerio, Waxman Aaron B, Perchenet Loïc, Strait James, Xing Aiwen, Johnson-Levonas Amy O, Cornell Alexandra G, de Oliveira Pena Janethe, Ardeschir Ghofrani H
Division of Cardiovascular Medicine, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
Pulmonary Hypertension Center, University of Colorado, Anschutz Medical Campus, Aurora, Colorado.
J Heart Lung Transplant. 2025 Apr;44(4):609-624. doi: 10.1016/j.healun.2024.11.037. Epub 2024 Dec 5.
This analysis examined the effects of the activin signaling inhibitor, sotatercept, in pulmonary arterial hypertension (PAH) subgroups stratified by baseline cardiac index (CI).
Pooled data from PULSAR (N = 106; NCT03496207) and STELLAR (N = 323; NCT04576988) were analyzed using 2 different CI thresholds, <2.0 and ≥2.0 liter/min/m as well as <2.5 and ≥2.5 liter/min/m. Median changes from baseline at week 24 were evaluated using Hodges-Lehmann estimator and least squares (LS) means, with 95% confidence intervals and p-values (significance: p = 0.05). Categorial endpoints and time-to-clinical worsening were analyzed by Cochran-Mantel-Haenszel and Cox model respectively.
Of 429 participants, 51 had CI <2.0 and 378 ≥2.0 liter/min/m, while 179 had CI <2.5 and 250 ≥2.5 liter/min/m. Sotatercept significantly improved median 6-minute walk distance (range: 33.9 to 63.7 m: p < 0.001), pulmonary vascular resistance (range: -202.8 to -395.4 dyn•s•cm; p ≤ 0.002), and N-terminal pro-B-type natriuretic peptide (range: -317.3 to -1,041.2 pg/ml; p < 0.001) across subgroups. LS means showed reductions in pulmonary and right atrial pressures, decreased right ventricular size, and improved tricuspid annular plane systolic excursion/systolic pulmonary artery pressure. Sotatercept delayed time to first occurrence of death or a worsening event for CI ≥2.5 (hazard ratio [HR] 0.12; p < 0.001), ≥2.0 (HR 0.13; p < 0.001), and <2.5 (HR 0.21; p < 0.001) liter/min/m. Improvements were observed in WHO functional class (all p < 0.050) and ESC/ERS risk scores (all p < 0.001).
Sotatercept demonstrated consistent efficacy and safety across CI subgroups, supporting its use in PAH patients irrespective of baseline cardiac hemodynamics.
本分析研究了激活素信号抑制剂索他西普对按基线心脏指数（CI）分层的肺动脉高压（PAH）亚组的影响。
使用两种不同的CI阈值，即<2.0和≥2.0升/分钟/米²以及<2.5和≥2.5升/分钟/米²，对来自PULSAR（N = 106；NCT03496207）和STELLAR（N = 323；NCT04576988）的汇总数据进行分析。使用霍奇斯-莱曼估计量和最小二乘法（LS）均值评估第24周时相对于基线的中位数变化，并给出95%置信区间和p值（显著性：p = 0.05）。分别通过 Cochr an-Mantel-Haenszel检验和Cox模型分析分类终点和临床恶化时间。
在429名参与者中，51人的CI<2.0，378人的CI≥2.0升/分钟/米²，而179人的CI<2.5，250人的CI≥2.5升/分钟/米²。索他西普在各亚组中均显著改善了中位数6分钟步行距离（范围：33.9至63.7米；p<0.001）、肺血管阻力（范围：-202.8至-395.4达因•秒•厘米⁻⁵；p≤0.002）和N末端B型利钠肽原（范围：-317.3至-1041.2皮克/毫升；p<0.001）。LS均值显示肺和右心房压力降低，右心室大小减小，三尖瓣环平面收缩期位移/收缩期肺动脉压改善。对于CI≥2.5（风险比[HR] 0.12；p<0.001）、≥2.0（HR 0.13；p<0.001）和<2.5（HR 0.21；p<0.001）升/分钟/米²的患者，索他西普延迟了首次发生死亡或恶化事件的时间。在世界卫生组织功能分级（所有p<0.050）和欧洲心脏病学会/欧洲呼吸学会风险评分（所有p<0.001）方面均观察到改善。
索他西普在CI亚组中显示出一致的疗效和安全性，支持其在PAH患者中的使用，无论基线心脏血流动力学如何。
