Bosentan therapy for pulmonary arterial hypertension related to connective tissue disease: a subgroup analysis of the pivotal clinical trials and their open-label extensions. [Ann Rheum Dis] Journal article

OBJECTIVE: Endothelin-1 (ET) is considered a central pathogenic factor in connective tissue diseases (CTD) such systemic sclerosis (SSc), leading to vasoconstriction, fibrosis, hypertrophy and inflammation. A frequent complication of CTD is pulmonary arterial hypertension (PAH), which has major impact on functioning and quality of life, and is associated with a particularly poor prognosis. We present a subgroup analysis that summarises experiences from the pivotal studies and their open-label extensions with the oral dual ET receptor antagonist bosentan in patients with PAH and CTD, mostly SSc and lupus erythematosus.
METHODS: Sixty-six patients with PAH/CTD, in WHO functional class III or IV, were randomised to two double-blind, placebo-controlled studies and followed for 12 and 16 weeks, respectively. The primary endpoint was change in exercise capacity, assessed with the 6- minute walk test. In both studies and their extensions, survival was assessed from start of treatment to death or data cut-off and analysed as Kaplan-Meier estimates.
RESULTS: The 44 PAH/CTD patients on bosentan were stable in 6-minute walk distance at study end (+19.5m, 95% CI: -3.2; 42.2), while placebo patients deteriorated (-2.6m, 95% CI: 54.0; 48.7). Sixty-four patients subsequently received bosentan in an open-label long-term extension study. Mean exposure to bosentan was 1.6 +/- 0.9 years, and mean duration of observation was 1.8 +/- 0.8 years. Eight patients (16%) received epoprostenol as add-on therapy and 7 patients (14%) after discontinuation of bosentan. Survival on bosentan was 85.9% after 1 year, and 73.4% after 2 years.
CONCLUSION: Short-term bosentan treatment in a CTD subgroup of PAH patients appears to have a favourable effect compared to placebo. The long term follow-up of these patients suggests that first-line bosentan, with the subsequent addition of other PAH therapies if required, is safe for long term treatment and may have a positive effect on outcome.

Ann Rheum Dis