In patients with pulmonary arterial hypertension (PAH), high levels of platelet endothelial cell adhesion molecule 1 (PECAM-1) are associated with less improvement in 6-minute walk distance (6MWD) and may also be predictive of response to treprostinil therapy. A post hoc biomarker analysis1 of the 16-week, randomized controlled FREEDOM-C2 study2 of oral treprostinil in patients receiving background treatment with an endothelial receptor antagonist and/or phosphodiesterase type 5 inhibitor results were published in The American Journal of Cardiology.
In the current analysis, investigators sought to identify novel biomarkers that could predict treatment response and risk in patients with PAH. They performed their analysis in the subgroup of patients with a baseline biomarker measurement, which was available in 173 of the total 310 individuals enrolled in the FREEDOM-C2 trial (ClinicialTrials.gov Identifier: NCT00887978). Overall, 61.8% (107 of 173) of those evaluated had idiopathic or familial PAH, and 35.3% (61 of 173) had connective tissue disease (CTD)-associated PAH (CTD-PAH). Overall, the majority of participants had World Health Organization (WHO) class III symptoms (75.6%; 130 of 172 individuals).
As PAH is known to be associated with endothelial dysfunction, serum levels of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 1 (VEGFR-1), PECAM-1, E-selectin, Endoglin, and P-selectin were measured at the initiation of the study and then at 16 weeks. Protein levels were linked to WHO functional status; 6MWD at baseline and change over 16 weeks; and a composite end point of clinical worsening, death, hospitalization, reduction of >20% in 6MWD or the addition of PAH treatment by 16 weeks.
Results of the study showed that only levels of PECAM-1 were significantly associated with the composite clinical end point, when adjusting for age and CTD-PAH via multivariate logistic regression, compared with non–CTD-PAH (P =.001). Moreover, patients with high (ie, >58 ng/mL) PECAM-1 levels were significantly older than those with low (ie, <58 ng/mL) PECAM levels (median age, 52 years vs 48 years, respectively; P <.05). No significant differences were reported with respect to sex, etiology of PAH, or baseline 6MWD, however, according to PECAM-1 level. Patients with high PECAM-1 levels at baseline exhibited significantly lower increases in 6MWD compared with those with low PECAM-1 levels at baseline (median, 4 months vs 26 months, respectively; P <.01).
Regarding change in PECAM-1 levels from baseline, a significant decrease in PECAM-1 concentrations was observed in the active treatment group (-6.6 ng/mL vs -1.2 ng/mL, respectively; P <.01). Furthermore, a significant association was demonstrated between active treatment and median change in 6MWD (P <.01) in patients in the group with high PECAM-1 levels, but not in those with low PECAM-1 levels.
The researchers concluded that further investigation is warranted to evaluate whether PECAM-1 levels may help identify both those individuals with PAH who are in need of additional treatment and those who would benefit most from the therapy.
1. Clapham K, Rao Y, Sahay S, et al. PECAM-1 is associated with outcomes and response to treatment in pulmonary arterial hypertension [published online April 29, 2020]. Am J Cardiol. doi:10/1016/j.amjcard.2020.04.031
2. Tapson VF, Jing Z-C, Xu K-F, et al; on behalf of the FREEDOM-C2 Study Team. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. CHEST. 2013;144(3):952-958.