Treatment with Oral or Inhaled Treprostinil in Patients with Pulmonary Arterial Hypertension and Cardiovascular Comorbidities

R James White; Karim El-Kersh; Stephan Rosenkranz; Veronica Franco; Carmine Dario Vizza; Roberto Badagliacca; Joanna Pepke-Zaba; Jean Elwing; Rahul G Argula; Shelley Shapiro; Hyoshin Kim; Scott Seaman; Eric Shen; Manisit Das; Meredith Broderick; Vallerie McLaughlin

doi:10.1016/j.chest.2024.11.027

Treatment with Oral or Inhaled Treprostinil in Patients with Pulmonary Arterial Hypertension and Cardiovascular Comorbidities

Chest. 2024 Nov 30:S0012-3692(24)05604-6. doi: 10.1016/j.chest.2024.11.027. Online ahead of print.

Authors

R James White¹, Karim El-Kersh², Stephan Rosenkranz³, Veronica Franco⁴, Carmine Dario Vizza⁵, Roberto Badagliacca⁵, Joanna Pepke-Zaba⁶, Jean Elwing⁷, Rahul G Argula⁸, Shelley Shapiro⁹, Hyoshin Kim¹⁰, Scott Seaman¹⁰, Eric Shen¹⁰, Manisit Das¹⁰, Meredith Broderick¹⁰, Vallerie McLaughlin¹¹

Affiliations

¹ University of Rochester Medical Center, Rochester, NY 14642, USA.
² Division of Pulmonary Critical Care and Sleep Medicine, Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ, USA.
³ Department of Cardiology and Cologne Cardiovascular Research Center (CCRC), Heart Center at the University Hospital Cologne, Cologne, Germany. Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine, University of Cologne, Cologne, Germany.
⁴ The Ohio State University, Columbus, OH, USA.
⁵ Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, Rome, Italy.
⁶ Papworth Hospital NHS Foundation Trust, Pulmonary Vascular Disease Unit, Cambridge, Cambridgeshire, UK.
⁷ Division of Pulmonary, Critical Care, and Sleep Medicine University of Cincinnati, Cincinnati, Ohio, USA.
⁸ Medical University of South Carolina, Charleston, SC, USA.
⁹ Division of Cardiology, VA Greater Los Angeles Healthcare System and Division of Pulmonary Critical Care, David Geffen UCLA School of Medicine, Los Angeles, CA, USA.
¹⁰ United Therapeutics, Research Triangle Park, NC, USA.
¹¹ University of Michigan, Ann Arbor, MI, USA. Electronic address: vmclaugh@med.umich.edu.

PMID: 39622469
DOI: 10.1016/j.chest.2024.11.027

Abstract

Background: An increasing number of patients with pulmonary arterial hypertension (PAH) have cardiovascular comorbidities. However, the effects of comorbidities on responses to PAH treatment are not well understood.

Research question: Do cardiovascular comorbidities in patients with PAH influence the efficacy and tolerability of inhaled or oral treprostinil?

Study design and methods: All patients from phase 3 studies TRIUMPH (N = 235) and FREEDOM-EV (N = 690) were included in this post hoc analysis and were classified as having 0, ≥1, or ≥2 cardiovascular comorbidities of interest based on patients' medical histories. The mean difference in 6-minute walk distance (6MWD) and N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to Week 12 was assessed for TRIUMPH and the risk and incidence of clinical worsening was assessed for patients in FREEDOM-EV. Adverse events (AEs) were summarized for each comorbidity grouping for TRIUMPH and FREEDOM-EV.

Results: In TRIUMPH, there were 79, 156, and 88 patients with 0, ≥1, and ≥2 comorbidities, respectively. Patients on inhaled treprostinil had improvements in 6MWD, with numerically similar improvements for comorbidity subgroups (0: 26 m, P = 0.020; ≥1: 22 m, P = 0.006; ≥2: 21.6 m, P = 0.043). Significant reductions in NT-proBNP were also seen in all subgroups. In FREEDOM-EV, there were 375, 315, and 166 patients with 0, ≥1, and ≥2 comorbidities, respectively. Regardless of comorbidities, patients on oral treprostinil had a significantly reduced risk of clinical worsening compared with placebo (0: 36% reduction, P = 0.034; ≥1: 41% reduction, P = 0.014; ≥2: 45% reduction, P = 0.026). In TRIUMPH and FREEDOM-EV, AE profiles were typical for this class of medication regardless of the number of comorbidities. A sensitivity analysis using a subset of comorbidities confirmed the findings of our primary analysis.

Interpretation: This post hoc analysis suggests that patients with PAH and cardiovascular comorbidities can benefit from combination therapy with inhaled or oral treprostinil.

Keywords: cardiac; comorbidity; pulmonary arterial hypertension; treprostinil.