Relevance of angiopoietin-2 and soluble P-selectin levels in patients with pulmonary arterial hypertension receiving combination therapy with oral treprostinil: a FREEDOM-C2 biomarker substudy

Abstract

Studies have suggested roles for angiopoietin-2 (Ang-2) and soluble P-selectin (sP-selectin) as biomarkers of disease severity and treatment response in pulmonary arterial hypertension (PAH), but additional data are required for validation. We evaluated these biomarkers using data from FREEDOM-C2, in which patients with PAH receiving stable monotherapy or combination therapy were randomized to receive additional treatment with oral treprostinil (up-titrated from 0.25 mg twice daily) or placebo for 16 weeks. Biomarker analysis was optional in FREEDOM-C2. We measured plasma Ang-2 and sP-selectin levels at baseline and at week 16, and we assessed their association with predefined outcomes (6-minute walk distance [6MWD] change from baseline >40 m, 6MWD >380 m, functional class I/II, and/or N-terminal pro-brain natriuretic peptide [NT-proBNP] <1,800 pg/mL at week 16) using Spearman correlation, receiver operating characteristics, and logistic regression. Biomarker data were available for 83 of 157 and 95 of 153 patients in the oral treprostinil and placebo groups, respectively. In the oral treprostinil group, baseline Ang-2 levels correlated with week 16 NT-proBNP levels (P < 0.0001). Baseline Ang-2 ≥12 ng/mL was associated with a reduced likelihood of having NT-proBNP <1,800 pg/mL at week 16 (multivariate odds ratio: 0.08; 95% confidence interval: 0.02-0.32). However, Ang-2 showed no significant association with the other assessed outcomes, and sP-selectin was not associated or correlated with any of the outcomes. These data suggest that Ang-2 and sP-selectin are not associated with response to oral treprostinil in patients already receiving stable PAH therapy.

Trial registration: Clinicaltrials.gov identifier NCT00887978.

Keywords: angiopoietin-2; granule membrane protein 140; prostacyclin; pulmonary hypertension.

Figures

Figure 1

Treatment response at week 16 for patients receiving oral treprostinil (subset with available data on angiopoietin-2 and soluble P-selectin; n = 83). 6MWD: 6-minute walk distance; NT-proBNP: N-terminal pro-brain natriuretic peptide; NYHA: New York Heart Association; WHO: World Health Organization.

Figure 2

Scatter plot showing the relationship between Ang-2 concentration at baseline and NT-proBNP concentration at week 16 for patients receiving oral treprostinil (subset with available data on Ang-2 and NT-proBNP; n = 78). Ang-2: angiopoietin-2; NT-proBNP: N-terminal pro-brain natriuretic peptide.