Chest
Volume 121, Issue 6, June 2002, Pages 1860-1868
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Clinical Investigations
Pulmonary Hypertension
Clinical Efficacy of Sitaxsentan, an Endothelin-A Receptor Antagonist, in Patients With Pulmonary Arterial Hypertension: Open-Label Pilot Study

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Study objectives

To evaluate the safety and efficacy of sitaxsentan, an endothelin-A receptor antagonist, in a 12-week, open-label trial of patients with pulmonary arterial hypertension (PAH).

Patients

Six children and 14 adults with New York Heart Association (NYHA) functional class II, III, or IV primary pulmonary hypertension or PAH associated with either congenital systemic-to-pulmonary shunts or collagen vascular disease were enrolled.

Measurements

Sitaxsentan was administered orally at 100 to 500 mg bid for 12 weeks. Cardiopulmonary hemodynamics via cardiac catheterization were obtained at baseline and week 12. Six-minute walk test distance was measured at baseline, week 6, and week 12.

Results

Sitaxsentan treatment resulted in significant improvement in exercise capacity as assessed by the 6-min walk distance (baseline [mean ± SD], 466 ± 132 m; week 12, 515 ± 141 m, n = 20, p = 0.006). Mean pulmonary artery pressure and pulmonary vascular resistance index also improved (63 ± 20 to 52 ± 22 mm Hg, n = 17, p = 0.0002; and 20 ± 11 to 14 ± 13 U × m2, n = 17, p = 0.008, respectively). Serious adverse events included two cases of acute hepatitis (fatal in one patient).

Conclusions

Patients with NYHA functional class II, III, or IV PAH showed a significant improvement in exercise capacity and cardiopulmonary hemodynamics over a 12-week period of treatment with sitaxsentan, an endothelin-A receptor antagonist. Further investigation is warranted to evaluate the safety and efficacy of sitaxsentan in patients with PAH.

Section snippets

Patient Selection

After institutional review board approval was obtained and informed consent signed, 6 children and 14 adults with primary pulmonary hypertension or PAH associated with either congenital systemic-to-pulmonary shunts or collagen vascular disease were enrolled in this study. Inclusion criteria were: (1) NYHA functional class II, III, or IV; (2) mean pulmonary artery pressure (PAPm) ≥ 25 mm Hg at rest, mean pulmonary capillary wedge pressure or left ventricular end-diastolic pressure ≤ 15 mm Hg,

Baseline Characteristics

The baseline demographic and hemodynamic characteristics are shown in Table 1. Six children and 14 adults were enrolled; 8 patients had primary pulmonary hypertension and 12 patients had PAH associated with either congenital systemic-to- pulmonary shunts (n = 10) or collagen vascular disease (n = 2). Fourteen patients were female and 6 patients were male. Mean ( ± SD) age was 36 ± 21 years (range, 7 to 68 years), and mean weight was 59 ± 19 kg (range, 25 to 87 kg).

Exercise Capacity

Despite a wide range of

Discussion

Sitaxsentan, a selective ET-A receptor antagonist, improved exercise capacity and cardiopulmonary hemodynamics in children and adults with PAH. In contrast to previous experience with epoprostenol,5,6,7,8 which has its greatest effect on cardiac output, sitaxsentan appears to have a greater effect on lowering pulmonary artery pressure than its effect on cardiac output. In contrast, similar to the experience with epoprostenol, the data from the first PAH bosentan trial also showed a greater

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  • Cited by (0)

    Support was provided by the National Institutes of Health, National Center for Research Resources (RR-00645); Texas Biotechnology Corporation, Houston, TX; and ICOS Corporation, Bothell, WA.

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