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Presentation Number: 1862
PURPOSE: Bosentan, a dual endothelin (ETA/ETB) receptor antagonist, was reported to improve exercise capacity and delay clinical worsening in placebo-controlled clinical trials (maximum duration was 6 months) in a population including patients with idiopathic pulmonary arterial hypertension (iPAH) and PAH-CTD (1,2). The present study was designed to evaluate the long-term effects of bosentan on the quality of life (QOL) and survival of patients with PAH-CTD.
METHODS: In this open-label, single-arm, prospective study, 53 patients with PAH-CTD in WHO functional class III received bosentan (62.5 mg bid for 4 weeks then 125 mg bid) for a planned duration of 48 weeks. Study assessments at Week 48 included WHO functional class, quality of life (Short-Form Health Survey [SF-36] and Scleroderma Health Assessment Questionnaire [SHAQ]). The Kaplan-Meier (KM) estimates for time to clinical worsening (death or hospitalization due to PAH, need for prostanoids, lung transplantation), and to death were calculated up to week 48.
RESULTS: At baseline, the patients (83% women) had a mean age of 63 ± 13 years (± SD). Patients had limited (lSSc, 55%) or diffuse (dSSc, 25%) systemic sclerosis, overlap CTD (11%) or systemic lupus erythematosus (SLE, 9%). At Week 48, WHO class improved in 27% of patients (95% confidence interval (CI): 16%-42%) and was unchanged in 57% (95% CI: 42%-71%). The overall KM estimate for absence of clinical worsening was 68% (95% CI: 55%-82%), (100% for SLE, 75% for dSSc, 67% for overlap CTD, and 61% for lSSc). The SF-36 health transition score improved in each etiology subgroup, with overall improvement of -0.80 ± 0.22 (p = 0.001). Improvement was reported in 57% of patients (95% CI: 41%-71%) and no change in 26% (95% CI: 14%-41%). The SHAQ disability index remained stable. The overall KM estimate for survival at week 48 was 92% (95% CI: 85%-100%). Four patients died (2 with lSSc, 1 with dSSc, and 1 with overlap CTD). Serious adverse events (all unrelated to study medication) were reported in 24 patients. Bosentan was well tolerated, with a safety profile comparable to that previously reported.
CONCLUSIONS: Bosentan therapy for 48 weeks led to improvement or stabilization of PAH symptoms and QoL in a majority of patients with PAH-CTD. Survival rate was 92%. Hence, this prospective study in patients with various types of PAH-CTD confirms clinical benefits of bosentan treatment previously observed in subpopulations of two short-term placebo controlled trials and also provides additional evidence of long-term benefit for quality of life and survival.
References
1. Channick RN et al. Lancet 2001 Oct 6;358(9288):1119-23
2. Rubin LJ et al. N Engl J Med 2002; 346:896-903.
METHODS: In this open-label, single-arm, prospective study, 53 patients with PAH-CTD in WHO functional class III received bosentan (62.5 mg bid for 4 weeks then 125 mg bid) for a planned duration of 48 weeks. Study assessments at Week 48 included WHO functional class, quality of life (Short-Form Health Survey [SF-36] and Scleroderma Health Assessment Questionnaire [SHAQ]). The Kaplan-Meier (KM) estimates for time to clinical worsening (death or hospitalization due to PAH, need for prostanoids, lung transplantation), and to death were calculated up to week 48.
RESULTS: At baseline, the patients (83% women) had a mean age of 63 ± 13 years (± SD). Patients had limited (lSSc, 55%) or diffuse (dSSc, 25%) systemic sclerosis, overlap CTD (11%) or systemic lupus erythematosus (SLE, 9%). At Week 48, WHO class improved in 27% of patients (95% confidence interval (CI): 16%-42%) and was unchanged in 57% (95% CI: 42%-71%). The overall KM estimate for absence of clinical worsening was 68% (95% CI: 55%-82%), (100% for SLE, 75% for dSSc, 67% for overlap CTD, and 61% for lSSc). The SF-36 health transition score improved in each etiology subgroup, with overall improvement of -0.80 ± 0.22 (p = 0.001). Improvement was reported in 57% of patients (95% CI: 41%-71%) and no change in 26% (95% CI: 14%-41%). The SHAQ disability index remained stable. The overall KM estimate for survival at week 48 was 92% (95% CI: 85%-100%). Four patients died (2 with lSSc, 1 with dSSc, and 1 with overlap CTD). Serious adverse events (all unrelated to study medication) were reported in 24 patients. Bosentan was well tolerated, with a safety profile comparable to that previously reported.
CONCLUSIONS: Bosentan therapy for 48 weeks led to improvement or stabilization of PAH symptoms and QoL in a majority of patients with PAH-CTD. Survival rate was 92%. Hence, this prospective study in patients with various types of PAH-CTD confirms clinical benefits of bosentan treatment previously observed in subpopulations of two short-term placebo controlled trials and also provides additional evidence of long-term benefit for quality of life and survival.
References
1. Channick RN et al. Lancet 2001 Oct 6;358(9288):1119-23
2. Rubin LJ et al. N Engl J Med 2002; 346:896-903.
C.P. Denton, Actelion Pharmaceuticals, Allschwil, Switzerland, 5 Consulting fees.