Chest
Volume 134, Issue 4, October 2008, Pages 775-782
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Original Research
Pulmonary Arterial Hypertension
Sitaxsentan for the Treatment of Pulmonary Arterial Hypertension: A 1-Year, Prospective, Open-Label Observation of Outcome and Survival

https://doi.org/10.1378/chest.07-0767Get rights and content

Background

Despite advances in the management of pulmonary arterial hypertension (PAH), the mortality rate remains excessive. Long-term efficacy evaluations are needed to guide therapeutic management. The purpose of this study is to present 1-year observational data with two endothelin antagonists, sitaxsentan and bosentan, in a prospective, open-label study.

Methods

The present study was a prospective, international, multicenter, randomized, open-label extension of the Sitaxsentan To Relieve Impaired Exercise-2 trial. All-cause mortality, time to discontinuation (all causes) from monotherapy, time to discontinuation due to adverse events, time to elevations in and time to discontinuation due to elevated hepatic transaminases, and time to first clinical worsening event were evaluated. Patients initially receiving sitaxsentan at 50 mg were excluded from the main analysis. The distributions of time-to-event variables are estimated using Kaplan-Meier methods, and treatment effects are evaluated using the Cox proportional hazards model.

Results

Patients treated with sitaxsentan at 100 mg had 96% overall survival and a 34% risk for a clinical worsening event by 1 year. In addition, there was a 6% risk of elevated aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels > 3 × upper limit of normal range (ULN) at 1 year and a 15% risk of discontinuation due to adverse events. Patients treated with bosentan had 88% overall survival and a 40% risk of a clinical worsening event by 1 year. In addition, there was a 14% risk for elevated AST and/or ALT levels > 3 × ULN at 1 year and a 30% risk of discontinuation due to adverse events.

Conclusions

At 1 year, sitaxsentan therapy appears safe and efficacious for patients with PAH; reductions in mortality and the risk for clinical worsening events provide support for durability of efficacy.

Section snippets

Patients

Two hundred twenty-nine patients aged 12 to 78 years in WHO functional class II-IV with idiopathic PAH (IPAH) or PAH associated with connective tissue disease (PAH-CTD) or PAH associated with a congenital heart defect (PAH-CHD) were enrolled in STRIDE-2X. Additional inclusion criteria have been published previously.7 The study was conducted according to ethical principles stated in the Declaration of Helsinki (1996) and applicable guidelines on good clinical practice. The protocol was approved

Demographics

The sitaxsentan and bosentan treatment groups in the analysis population were comparable with regards to baseline characteristics (Table 1). Patients ranged in age from 14 to 78 years (mean, 54 years), and approximately 77% were female. Approximately 60% of patients had IPAH, 30% had PAH-CTD, and 10% had PAH-CHD. Baseline characteristics of patients in predefined subgroups were similar.

The overall treatment population of 229 patients was randomized to sitaxsentan (n = 145) or standard-dose

Discussion

We report 1-year results with the selective ET-A receptor antagonist sitaxsentan coupled with 1-year outcomes with the nonselective ET-A/ET-B receptor antagonist bosentan in a broad class of PAH patients (inclusion of IPAH [approximately 60%] and associated PAH conditions, ie, PAH-CTD [approximately 30%] and PAH-CHD [approximately 10%] with baseline functional class II-IV). It is important to recognize that although the STRIDE-2X study looked at patients who initiated treatment with sitaxsentan

References (21)

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Cited by (97)

  • Hemodynamic Stability After Transitioning Between Endothelin Receptor Antagonists in Patients With Pulmonary Arterial Hypertension

    2013, Canadian Journal of Cardiology
    Citation Excerpt :

    Transition from the selective ERA sitaxsentan to nonselective ERAs did not result in any significant changes in hemodynamics over the 17-week follow-up period when the patients were analyzed as a group. No ERA has been shown to be definitively superior to another and our hemodynamic data support the no-difference hypothesis.10 This may simply mean that the pharmacological effects of the different agents are similar.

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The authors have no conflicts of interest to disclose.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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