Chest
Volume 124, Issue 1, July 2003, Pages 247-254
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Clinical Investigations
Pulmonary Circulation
Effects of the Dual Endothelin Receptor Antagonist Bosentan in Patients With Pulmonary Arterial Hypertension: A 1-Year Follow-up Study

https://doi.org/10.1378/chest.124.1.247Get rights and content

Study objectives

We report on the long-term safety and efficacy of bosentan treatment in patients with pulmonary arterial hypertension (PAH).

Background

In a preceding study, bosentan was well tolerated and significantly improved the exercise capacity and hemodynamics of patients with PAH after 12 weeks of treatment.

Design

The present study was an open-label extension to the preceding double-blind, placebo-controlled study of 32 patients with PAH (primary or associated with scleroderma) who received bosentan or placebo at 125 mg bid for 3 to 7 months.

Patients

Twenty-nine of the original 32 patients received bosentan for an additional year (62.5 mg bid for 4 weeks and then 125 mg bid).

Interventions

Study end points included long-term safety, 6-min walk distance at week 4, modified New York Heart Association (NYHA) functional class of PAH at month 12, and the occurrence of withdrawal due to clinical worsening. Additional exploratory analyses included a walk test at month 6 for 19 patients and hemodynamic assessment at month 12 for 11 patients.

Results

At month 6, assessed patients continuing bosentan treatment maintained the improvement in walk distance observed at the end of the previous study (mean ± SEM, 60 ± 11 m), and patients starting bosentan treatment improved their walk distance by 45 ± 13 m. Long-term treatment with bosentan for > 1 year was associated with an improvement in hemodynamic parameters and modified NYHA functional class. Overall, bosentan treatment was well tolerated. No patient underwent transplantation or died.

Conclusions

Long-term treatment with bosentan is safe and has sustained benefits on exercise capacity and hemodynamics in patients with PAH.

Section snippets

Patient Selection

All eligible patients had participated in the preceding double-blind, placebo-controlled clinical study involving 3 to 7 months of treatment with 125 mg bid of bosentan or placebo.1920 Inclusion/exclusion criteria for the preceding study have been described previously.1920 Briefly, patients had symptomatic, severe PPH or PH associated with scleroderma in functional classes III-IV (according to the modified New York Heart Association [NYHA] classification,5 which ranks PAH severity in classes I

Results

Of the 32 patients randomized in the preceding study to receive bosentan or placebo (2:1 ratio), 3 patients from the placebo group did not participate in the open-label study due to clinical worsening of PAH (Fig 1). Of the 29 enrolled patients, 21 patients had received bosentan in the preceding study (“ex-bosentan”; 100% of the eligible bosentan-treated patients) and 8 patients had received placebo in the preceding study (“ex-placebo”; 73% of the eligible placebo-treated patients). All 29

Discussion

The present study is the first trial investigating the long-term safety and efficacy of bosentan in the treatment of PAH. In the preceding double-blind, placebo-controlled study, bosentan demonstrated favorable hemodynamic effects—including decreases in pulmonary pressures and resistances—after 3 months of treatment. These effects were accompanied by an increase in exercise capacity, an improvement in functional class, and a reduction in the incidence of clinical deterioration.1920 In this

Appendix

Olivier Sitbon, MD; David B. Badesch, MD; Richard N. Channick, MD; Adaani Frost, MD; Ivan M. Robbins, MD; Victor F. Tapson, MD; Gérald Simonneau, MD; and Lewis J. Rubin, MD, contributed to study recruitment and assessments, and to the preparation of the article. Dr. Sitbon collected long-term hemodynamic data. Frédéric Bodin, MD; Maurizio Rainizio, PhD; and Sébastien Roux, MD, designed the study, monitored the clinical and laboratory assessments, performed the study analysis, and contributed to

ACKNOWLEDGMENT

We thank all of the local investigators and their staff; Annie Pelissier from Université de Bicêtre, Bicêtre, France; Chris Stevens, Kris Wynne, Betty Booker, Karen Fagan, and Bertron Groves from University of Colorado Health Sciences Center, Denver, CO; Katie Kinninger from the Division of Pulmonary and Critical Care Medicine, University of California San Diego, CA; Helena Purl from Baylor College of Medicine and the Methodist Hospital, Houston, TX; Wendi R. Mason from Vanderbilt University

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    This study was supported by Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.

    The authors are consultants or investigators for Actelion Pharmaceuticals Ltd.

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