Selexipag for the treatment of chronic thromboembolic pulmonary hypertension

Abstract

Background: Treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) remain limited. Selexipag, an oral selective IP prostacyclin receptor agonist approved for pulmonary arterial hypertension, is a potential treatment option for CTEPH.

Methods: In this multicentre, randomised, double-blind, placebo-controlled study, 78 Japanese patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy and/or balloon pulmonary angioplasty were randomly assigned to receive placebo or selexipag. The primary end-point was the change in pulmonary vascular resistance (PVR) from baseline to week 20. Secondary end-points were changes in other haemodynamic parameters: 6-min walk distance (6MWD), Borg dyspnoea scale score, World Health Organization (WHO) functional class, EuroQol five-dimension five-level tool and N-terminal pro-brain natriuretic peptide.

Results: The change in PVR was -98.2±111.3 dyn·s·cm^-5 and -4.6±163.6 dyn·s·cm^-5 in the selexipag and placebo groups, respectively (mean difference -93.5 dyn·s·cm^-5; 95% CI -156.8 to -30.3; p=0.006). The changes in cardiac index (p<0.001) and Borg dyspnoea scale score (p=0.036) were also significantly improved over placebo. 6MWD and WHO functional class were not significantly improved. The common adverse events in the selexipag group corresponded to those generally observed following administration of a prostacyclin analogue.

Conclusion: Selexipag significantly improved PVR and other haemodynamic variables in patients with CTEPH, although exercise capacity remained unchanged. Further large-scale investigation is necessary to prove the role of selexipag in CTEPH.

FIGURE 1

Schematic of study design. 200 μg of the study drug was administered twice daily and titrated according to individual tolerance. Dose reduction and re-uptitration were allowed during the titration period.

FIGURE 2

Patient disposition. ^#: if data at 20 weeks of treatment were missing, the missing data were imputed by baseline observation carried forward, last observation carried forward, or worst value (in the case of pulmonary hypertension worsening) and the data that included the imputed data served as the data at the end of the study.

FIGURE 3

Change in pulmonary vascular resistance (PVR) from baseline to week 20. Data are presented as mean±sd. The mean change from baseline to 20 weeks of treatment was −98.2 dyn·s·cm⁻⁵ (95% CI −134.2 to −62.1 dyn·s·cm⁻⁵) in the selexipag group and −4.6 dyn·s·cm⁻⁵ (95% CI −57.7 to 48.4 dyn·s·cm⁻⁵) in the placebo group. A significant treatment effect for selexipag versus placebo groups was observed (treatment effect −93.5, 95% CI −156.8 to −30.3; p=0.006 with the use of the Wilcoxon rank sum test). **: p<0.01.

FIGURE 4

Change from baseline in pulmonary vascular resistance (PVR) in baseline characteristics subgroup. ^#: pulmonary endarterectomy (PEA) not indicated because of distal organised thrombus; ^¶: persistent or recurrent pulmonary hypertension after PEA; ⁺: high-risk case (e.g. comorbidities and old age) or PEA could not be performed for other reasons. BPA: balloon pulmonary angioplasty; ERA: endothelin receptor antagonist; PDE5: phosphodiesterase type 5.