title: Long-term results from the EARLY study of bosentan in WHO functional class II pulmonary arterial hypertension patients.
abstract: 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.
authors: Service de Pneumologie, Hôpital Universitaire de Bicêtre, Université Paris-Sud, Le Kremlin Bicêtre, France. Electronic address: gerald.simonneau@abc.ap-hop-paris.fr.
authors: Gérald
authors: G
authors: Simonneau
authors: Institute of Cardiology, University of Bologna, Bologna, Italy.
authors: Nazzareno
authors: N
authors: Galiè
authors: Charles University, 1st Faculty of Medicine, 2nd Medical Department, Clinical Department of Cardiology and Angiology, Prague, Czech Republic.
authors: Pavel
authors: P
authors: Jansa
authors: Complexo Hospitalar Sta Casa de Porto Alegre, Porto Alegre, Brazil.
authors: Gisela Martina Bohns
authors: GM
authors: Meyer
authors: Institute of Clinical and Experimental Medicine-IKEM, Department of Cardiology, Prague, Czech Republic.
authors: Hikmet
authors: H
authors: Al-Hiti
authors: Clinical Development, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Andjela
authors: A
authors: Kusic-Pajic
authors: Effi-Stat, Paris, France.
authors: Jean-Christophe
authors: JC
authors: Lemarié
authors: Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.
authors: Marius M
authors: MM
authors: Hoeper
authors: Division of Pulmonary & Critical Care Medicine, University of California, San Diego, CA, USA.
authors: Lewis J
authors: LJ
authors: Rubin
mesh_terms: D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D018450:Disease Progression; D004311:Double-Blind Method; D005080:Exercise Test; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D013449:Sulfonamides / Q000627:therapeutic use*; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D013449:Sulfonamides; D000077300:Bosentan
keywords: Bosentan; Endothelin; Pulmonary arterial hypertension; Risk factors; Survival