Efficacy and Safety of Sotatercept Across Ranges of Cardiac Index in Patients with Pulmonary Arterial Hypertension: A Pooled Analysis of PULSAR and STELLAR

Mardi Gomberg-Maitland, George Washington University School of Medicine and Health Sciences, Washington, DC, USA. Electronic address: mgomberg@mfa.gwu.edu.
David B. Badesch, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
J Simon Gibbs, National Heart and Lung Institute, Imperial College London, London, UK.
Ekkehard Grünig, Thoraxklinik-Heidelberg and the German Center for Lung Research, Heidelberg, Germany.
Marius M. Hoeper, Hannover Medical School and the German Center for Lung Research, Hannover, Germany.
Marc Humbert, Université Paris-Saclay, INSERM Unité Mixte de Recherche en Santé 999, Hôpital Bicêtre (Assistance Publique-Hôpitaux de Paris), Le Kremlin-Bicêtre, France.
Grzegorz Kopeć, Department of Cardiac and Vascular Diseases, St. John Paul II Hospital in Krakow, Krakow, Poland; Pulmonary Circulation Centre, Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland.
Vallerie V. McLaughlin, University of Michigan, Ann Arbor, MI, USA.
Gisela Meyer, Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil.
Karen M. Olsson, Hannover Medical School and the German Center for Lung Research, Hannover, Germany.
Ioana R. Preston, Lahey Hospital and Medical Center, Burlington, MA, USA.
Stephan Rosenkranz, Department of Cardiology, and Cologne Cardiovascular Research Center (CCRC), Heart Center, University Hospital Cologne, Cologne, Germany.
Rogerio Souza, Instituto do Coração, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
Aaron B. Waxman, Brigham and Woman's Hospital, Boston, MA, USA.
Loïc Perchenet, Merck & Co., Inc., Rahway, NJ, USA.
James Strait, Merck & Co., Inc., Rahway, NJ, USA.
Aiwen Xing, Merck & Co., Inc., Rahway, NJ, USA.
Amy O. Johnson-Levonas, Merck & Co., Inc., Rahway, NJ, USA.
Alexandra G. Cornell, Merck & Co., Inc., Rahway, NJ, USA.
Janethe de Pena, Merck & Co., Inc., Rahway, NJ, USA.
H Ardeschir Ghofrani, Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.

Document Type

Journal Article

Publication Date

12-5-2024

Journal

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation

DOI

10.1016/j.healun.2024.11.037

Keywords

cardiac index; clinical trials; pulmonary arterial hypertension; sotatercept

Abstract

BACKGROUND: This analysis compared effects of the activin signaling inhibitor, sotatercept, across pulmonary arterial hypertension (PAH) subgroups stratified by baseline cardiac index (CI). METHODS: Pooled data from PULSAR (N=106; NCT03496207) and STELLAR (N=323; NCT04576988) were analyzed using two different CI thresholds, < and ≥ 2.0 L/min/m or 2.5 L/min/m. Median differences in change from baseline at week 24 were evaluated using Hodges-Lehmann (HL) estimator and mean differences by least squares (LS), with 95% confidence intervals and p-values; p=0.05 was significant. Categorial endpoints and time-to-clinical worsening were analyzed by Cochran-Mantel-Haenszel and Cox model (hazard ratio (HR), respectively, without multiplicity adjustment. RESULTS: Of 429 participants, 51 and 378 had CI <2.0 L/min/m and ≥ 2.0 L/min/m, respectively, whereas 179 and 250 had CI <2.5 L/min/m and ≥ 2.5 L/min/m, respectively. Across all CI subgroups, sotatercept vs placebo 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 -1041.2 pg/mL; p<0.001). LS means showed reductions in pulmonary and right atrial pressures, decreased right ventricular size and enhanced tricuspid annular plane systolic excursion/ systolic pulmonary artery pressure in all subgroups. Sotatercept significantly delayed time to first occurrence of death or a worsening event in the subset of participants with CI ≥2.5 (HR 0.12; p<0.001), ≥2.0 (HR 0.13; p<0.001), and <2.5 (HR 0.21; p<0.001) L/min/m. Improvements in World Health Organization functional class (all p<0.050) and European Society of Cardiology/European Respiratory Society risk score (all p<0.001) were seen within each subgroup. CONCLUSIONS: Efficacy and safety were consistent across baseline CI subgroups, supporting use of sotatercept in PAH patients irrespective of baseline cardiac hemodynamics.

Department

Medicine

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