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Clinical Trial
. 2022 Mar:193:106744.
doi: 10.1016/j.rmed.2022.106744. Epub 2022 Jan 19.

Oral treprostinil improves pulmonary vascular compliance in pulmonary arterial hypertension

Akram Khan  1 , R James White  2 , Gisela Meyer  3 , Tomas R Pulido Zamudio  4 , Carlos Jerjes-Sanchez  5 , Dana Johnson  6 , Rob Grover  6 , Meredith Broderick  6 , Aliou Ousmanou  6 , Louis Holdstock  6 , Evangelos Michelakis  7
Affiliations
Clinical Trial

Oral treprostinil improves pulmonary vascular compliance in pulmonary arterial hypertension

Akram Khan et al. Respir Med. 2022 Mar.

Abstract

Oral treprostinil has been shown to improve exercise capacity and delay disease progression in patients with pulmonary arterial hypertension (PAH), but its effects on hemodynamics are not well-characterized. The FREEDOM-EV trial was a Phase III, international, placebo-controlled, double-blind, event-driven study in 690 participants with PAH who were taking a single oral PAH therapy. FREEDOM-EV demonstrated a significantly reduced risk for clinical worsening with oral treprostinil taken three times daily and did not uncover new safety signals in PAH patients. Sixty-one participants in the FREEDOM-EV trial volunteered for a hemodynamics sub-study. Pulmonary artery compliance (PAC), a ratio of stroke volume to pulmonary pulse pressure, significantly increased from Baseline to Week 24 in the oral treprostinil group compared with the placebo group (geometric mean 26.4% active vs. -6.0% placebo; ANCOVA p=0.007). There was a significant increase in cardiac output in the oral treprostinil group compared to the placebo group (geometric mean 11.3% active vs. -6.4% placebo; ANCOVA p=0.005) and a corresponding significant reduction in pulmonary vascular resistance (PVR) (geometric mean -21.5 active vs. -1.8% placebo; ANCOVA p=0.02) from Baseline to Week 24. These data suggest that increased compliance contributes to the physiological mechanism by which oral treprostinil improves exercise capacity and delays clinical worsening for patients with PAH.

Keywords: Cardiac output; FREEDOM-EV; Hemodynamics; PVR; Right-heart catherization.

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Conflict of interest statement

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.
Fig. 1.
FREEDOM-EV Hemodynamic Sub-study. A) Mean (unadjusted) pulmonary arterial compliance increased by 44% from baseline to Week 24 in the oral treprostinil (n = 30) group versus 0% in the placebo (n = 24) group. Values represent means; error bars represent mean ± standard error B) Geometric mean (unadjusted) pulmonary vascular resistance dropped 21% from baseline to Week 24 in the oral treprostinil (n = 30) group versus 2% in the placebo (n = 24) group. Values represent geometric means; error bars represent geometric mean multiplied/divided by geometric standard error. C) Comparison of median dose for the hemodynamic sub-study to the total population of FREEDOM-EV over time. Error bars represent the 95% confidence interval. *p-value is obtained from the analysis of covariance with change from baseline in raw PAC as the dependent variable, treatment as fixed effect, and baseline raw PAC as a covariate. Ϯp-value is obtained from the analysis of covariance with change from baseline in log-transformed PVR as the dependent variable, treatment as fixed effect, and log-transformed baseline PVR as a covariate. PAC: pulmonary artery compliance; TID: three times a day; PVR: pulmonary vascular resistance.
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