Gérald Simonneau1, Nazzareno Galiè2, Pavel Jansa3, Gisela Martina Bohns Meyer4, Hikmet Al-Hiti5, Andjela Kusic-Pajic6, Jean-Christophe Lemarié7, Marius M Hoeper8, Lewis J Rubin9. 1. Service de Pneumologie, Hôpital Universitaire de Bicêtre, Université Paris-Sud, Le Kremlin Bicêtre, France. Electronic address: gerald.simonneau@abc.ap-hop-paris.fr. 2. Institute of Cardiology, University of Bologna, Bologna, Italy. 3. Charles University, 1st Faculty of Medicine, 2nd Medical Department, Clinical Department of Cardiology and Angiology, Prague, Czech Republic. 4. Complexo Hospitalar Sta Casa de Porto Alegre, Porto Alegre, Brazil. 5. Institute of Clinical and Experimental Medicine-IKEM, Department of Cardiology, Prague, Czech Republic. 6. Clinical Development, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. 7. Effi-Stat, Paris, France. 8. Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany. 9. Division of Pulmonary & Critical Care Medicine, University of California, San Diego, CA, USA.
Abstract
BACKGROUND: The double-blind phase of the EARLY study of bosentan remains the only randomized controlled trial of a PAH-targeted therapyin World Health Organization functional class (FC) II patients. We report on the efficacy, safety, disease worsening, survival and prognostic factors in mildly symptomatic pulmonary arterial hypertension (PAH) patients treated with bosentan in the open-label extension phase of the EARLY study. METHODS: Exploratory efficacy outcomes included 6-minute walk distance (6 MWD) and WHO FC. Adverse events were recorded. Kaplan-Meier analysis was used to estimate time to first PAH worsening event (death, initiation of intravenous or subcutaneous prostanoids, atrial septostomy or lung transplantation) and survival. Cox regression analysis determined factors prognostic of survival. RESULTS: Median exposure to bosentan (n=173) was 51 months. At the end of the bosentan-treatment assessment period, 77.8% of patients were in WHO FC I/II. Adverse events led to discontinuation of bosentan in 20.2% of patients. Aminotransferase elevations>3× upper limit of normal occurred in 16.8%. Four-year PAH-event-free survival and survival were 79.5% (95% confidence intervals [95% CI] 73.4, 85.6) and 84.8% [95% CI 79.4, 90.2], respectively. Low 6 MWD, low mixed venous oxygenation, high N-terminal pro hormone of brain natriuretic peptide levels and PAH associated with connective tissue disease were associated with a higher risk of death. CONCLUSIONS: The majority of patients exposed to long-term bosentan maintained or improved their functional class. Approximately 20% of the patients discontinued treatment because of adverse events, which were most commonly PAH worsening and elevated liver enzymes.
RCT Entities:
BACKGROUND: The double-blind phase of the EARLY study of bosentan remains the only randomized controlled trial of a PAH-targeted therapy in World Health Organization functional class (FC) II patients. We report on the efficacy, safety, disease worsening, survival and prognostic factors in mildly symptomatic pulmonary arterial hypertension (PAH) patients treated with bosentan in the open-label extension phase of the EARLY study. METHODS: Exploratory efficacy outcomes included 6-minute walk distance (6 MWD) and WHO FC. Adverse events were recorded. Kaplan-Meier analysis was used to estimate time to first PAH worsening event (death, initiation of intravenous or subcutaneous prostanoids, atrial septostomy or lung transplantation) and survival. Cox regression analysis determined factors prognostic of survival. RESULTS: Median exposure to bosentan (n=173) was 51 months. At the end of the bosentan-treatment assessment period, 77.8% of patients were in WHO FC I/II. Adverse events led to discontinuation of bosentan in 20.2% of patients. Aminotransferase elevations>3× upper limit of normal occurred in 16.8%. Four-year PAH-event-free survival and survival were 79.5% (95% confidence intervals [95% CI] 73.4, 85.6) and 84.8% [95% CI 79.4, 90.2], respectively. Low 6 MWD, low mixed venous oxygenation, high N-terminal pro hormone of brain natriuretic peptide levels and PAH associated with connective tissue disease were associated with a higher risk of death. CONCLUSIONS: The majority of patients exposed to long-term bosentan maintained or improved their functional class. Approximately 20% of the patients discontinued treatment because of adverse events, which were most commonly PAH worsening and elevated liver enzymes.
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