Clinical Research
Pulmonary Hypertension
Treatment of Pulmonary Arterial Hypertension With the Selective Endothelin-A Receptor Antagonist Sitaxsentan

https://doi.org/10.1016/j.jacc.2006.01.057Get rights and content
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Objectives

We sought to determine the optimal dose of the selective endothelin A (ETA) receptor antagonist sitaxsentan for the treatment of pulmonary arterial hypertension (PAH); for observation only, an open-label (OL) bosentan arm was included.

Background

Endothelin is a mediator of PAH. In a preliminary PAH study, the selective ETAreceptor antagonist sitaxsentan improved six-min walk (6MW) distance, World Health Organization (WHO) functional class (FC), and hemodynamics.

Methods

In this double-blind, placebo-controlled 18-week study, 247 PAH patients (idiopathic, or associated with connective tissue disease or congenital heart disease) were randomized; 245 patients were treated: placebo (n = 62), sitaxsentan 50 mg (n = 62) or 100 mg (n = 61), or OL (6MW tests, Borg dyspnea scores, and WHO FC assessments third-party blind) bosentan (n = 60). The primary end point was change in 6MW distance from baseline to week 18. Secondary end points included change in WHO FC, time to clinical worsening, and change in Borg dyspnea score.

Results

At week 18, patients treated with sitaxsentan 100 mg had an increased 6MW distance compared with the placebo group (31.4 m, p = 0.03), and an improved WHO FC (p = 0.04). The placebo-subtracted treatment effect for sitaxsentan 50 mg was 24.2 m (p = 0.07) and for OL bosentan, 29.5 m (p = 0.05). The incidence of elevated hepatic transaminases (>3× the upper limit of normal) was 6% for placebo, 5% for sitaxsentan 50 mg, 3% for sitaxsentan 100 mg, and 11% for bosentan.

Conclusions

Treatment with the selective ETAreceptor antagonist sitaxsentan, orally once daily at a dose of 100 mg, improves exercise capacity and WHO FC in PAH patients, with a low incidence of hepatic toxicity.

Abbreviations and Acronyms

ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
DSMB
Data Safety Monitoring Board
ET
endothelin
FC
functional class
INR
international normalized ratio
ITT
intent-to-treat
OL
open label
PAH
pulmonary arterial hypertension
6MW
six-min walk
STRIDE
Sitaxsentan To Relieve ImpaireD Exercise study
ULN
upper limit of normal
WHO
World Health Organization

Cited by (0)

Although none of the authors has significant stock ownership or other equity interests or patent licensing arrangements that might pose a conflict of interest in connection with the submitted article

1

Drs. Barst, Langleben, Badesch, Lawrence, Frost, Shapiro, Naeije, and Galie have served as consultants to the sponsor, Encysive Pharmaceutics, LP.