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Bosentan Improves Hemodynamics and Delays Time to Clinical Worsening in Patients with Mildly Symptomatic Pulmonary Arterial Hypertension: Results of the EARLY Study

Nazzareno Galiè


Lewis Rubin


Marius Hoeper


Pavel Jansa

A. Kusic-Pajic

G. Simmoneau

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Conference: 2008 International PHA Conference and Scientific Sessions

Release Date: 06.20.2008

Presentation Type: Abstracts

Galie N.1, Rubin L.J.2, Hoeper M.M.3, Jansa P.4, Kusic-Pajic A.5, Simmonneau G.6

1. Institute of Cardiology, University of Bologna, Bologna, Italy
2. University of California, San Diego, La Jolla, CA, USA
3. University of Hannover Medical School, Hannover, Germany
4. Centre for Pulmonary Hypertension, Charles University, Prague, Czech Republic
5. Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
6. Hôpital Antoine Béclère, Université Paris-Sud, Clamart, France

BACKGROUNDLimited data are available on the natural history and response to therapy of patients with mildly symptomatic (WHO functional class [FC] II) pulmonary arterial hypertension (PAH). The EARLY study was designed to assess the effects of treatment with bosentan, a dual endothelin receptor antagonist, exclusively in WHO FC II PAH patients.

METHODS: Patients ≥ 12 years with PAH (idiopathic or associated with HIV, congenital heart disease or connective tissue disease) were included; WHO class II, 6-minute walk distance (6MWD) < 80% normal, or < 500 m associated with a Borg dyspnea index of ³ 2 points. Patients were randomized 1:1 to placebo or bosentan (62.5 mg bid for 4 weeks and 125 mg bid thereafter) for 6 months. The co-primary endpoints were pulmonary vascular resistance (PVR) expressed as percent of baseline at month 6, and change from baseline to month 6 in 6MWD. Other endpoints included time to clinical worsening and hemodynamic parameters. Change from baseline in N-terminal-prohormone-brain natriuretic peptide (NT-proBNP) was an exploratory endpoint. Safety and tolerability were evaluated.

RESULTS185 patients were randomized (93 bosentan, 92 placebo). At 6 months, the PVR (geometric mean, 95% CI) was 83% (74, 94) and 107% (98, 118) of baseline value in the bosentan and placebo groups, respectively. This represented a treatment effect of -23% (95% CI: -34, -10; p < 0.0001) in favor of bosentan. The mean change (95% CI) from baseline in 6MWD at 6 months in the bosentan and placebo groups was +11 m (-5, 27) and -8 m (-24, 9), respectively, a treatment effect of +19 m (95% CI: 4, 42; p = 0.0758). Time to clinical worsening was significantly improved in patients treated with bosentan, with a 77% reduction in hazard (p [log-rank] = 0.0114). Improvements were also seen in other hemodynamic parameters and NT-proBNP. The safety and tolerability profile was consistent with that observed in previous placebo-controlled trials of bosentan in PAH.

CONCLUSIONSTreatment with bosentan in patients with mildly symptomatic (WHO functional class II) PAH resulted in significant reduction in PVR, a trend towards increase in exercise capacity that did not reach statistical significance, and an improvement in time to clinical worsening. These results suggest that early treatment of PAH may result in delay of disease progression.