Articles www.thelancet.com Vol 371 June 21, 2008 2093 Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial N Galiè, L J Rubin, M M Hoeper, P Jansa, H Al-Hiti, G M B Meyer, E Chiossi, A Kusic-Pajic, G Simonneau Summary Background Treatments for pulmonary arterial hypertension have been mainly studied in patients with advanced disease (WHO functional class [FC] III and IV). This study was designed to assess the effect of the dual endothelin receptor antagonist bosentan in patients with WHO FC II pulmonary arterial hypertension. Methods Patients with WHO FC II pulmonary arterial hypertension aged 12 years or over with 6-min walk distance of less than 80% of the normal predicted value or less than 500 m associated with a Borg dyspnoea index of 2 or greater were enrolled in this double-blind, placebo-controlled, multicentre trial. 185 patients were randomly assigned to receive bosentan (n=93) or placebo (n=92) for the 6-month double-blind treatment period via a centralised integrated voice recognition system. Primary endpoints were pulmonary vascular resistance at month 6 expressed as percentage of baseline and change from baseline to month 6 in 6-min walk distance. Analyses of the primary endpoints were done with all randomised patients who had a valid baseline assessment and an assessment or an imputed value for month 6. This trial was registered with ClinicalTrials.gov, number NCT00091715. Findings Analyses were done with 168 patients (80 in the bosentan group, 88 in the placebo group) for pulmonary vascular resistance and with 177 (86 and 91) for 6-min walking distance. At month 6, geometric mean pulmonary vascular resistance was 83·2% (95% CI 73·8–93·7) of the baseline value in the bosentan group and 107·5% (97·6–118·4) of the baseline value in the placebo group (treatment effect -22·6%, 95% CI -33·5 to -10·0; p<0·0001). Mean 6-min walk distance increased from baseline in the bosentan group (11·2 m, 95% CI –4·6 to 27·0) and decreased in the placebo group (–7·9 m, –24·3 to 8·5), with a mean treatment effect of 19·1 m (95% CI 3·6–41·8; p=0·0758). 12 (13%) patients in the bosentan group and eight (9%) in the placebo group reported serious adverse events, the most common of which were syncope in the bosentan group and right ventricular failure in the placebo group. Interpretation Bosentan treatment could be beneficial for patients with WHO FC II pulmonary arterial hypertension. Funding Actelion Pharmaceuticals Ltd. Introduction Pulmonary arterial hypertension is a devastating, progressive disease with increasingly debilitating symptoms. 1,2 Increased pulmonary vascular resistance results in extensive heart structural changes, limits patients exercise capacity and, eventually, leads to right heart failure and death. 2 Endothelin is a 21-aminoacid peptide that has a key role in the pathobiology of pulmonary arterial hypertension, 3,4 exerting vasoconstrictor and mitogenic effects by binding to two distinct receptor isoforms in the pulmonary vascular smooth muscle cells: endothelin A and B receptors. 5 Bosentan is an orally active dual (A and B) endothelin receptor antagonist that has been shown to improve exercise capacity, haemodynamics, and clinical worsening in two pivotal clinical trials. 6,7 In these studies, as well as in other trials of pulmonary arterial hypertension with bosentan 8,9 and other compounds, 10–22 most enrolled patients were in an advanced symptomatic state as testified by WHO functional class (WHO FC) at baseline. In fact, the proportion of enrolled patients in WHO FC III and IV in these trials ranged from 60% to 100%. 6–22 Observational studies suggest that there could be a clinical advantage to earlier initiation of treatment for pulmonary arterial hypertension. 23,24 However, the effect of pulmonary arterial hypertension treatments has never been explored exclusively in less compromised individuals (ie, those in WHO FC I and II). We present the results of the endothelin antagonist trial in mildly symptomatic pulmonary arterial hypertension patients (EARLY) study, a randomised controlled trial designed to assess the efficacy of the dual endothelin receptor antagonist bosentan in patients with WHO FC II pulmonary arterial hypertension. Methods Patients EARLY was a prospective, randomised, double-blind, multicentre, parallel group study done in 52 sites in 21 countries. Patients aged 12 years or over were enrolled if diagnosed with WHO FC II idiopathic pulmonary arterial hypertension, familial pulmonary arterial hypertension, or Lancet 2008; 371: 2093–100 See Comment page 2061 Institute of Cardiology, University of Bologna, Bologna, Italy (Prof N Galiè MD); University of California, San Diego, USA (Prof L J Rubin MD); Medizinische Hochschule, Hannover, Germany (Prof M M Hoeper MD); Charles University, 1st Faculty of Medicine, 2nd Medical Department, Clinical Department of Cardiology and Angiology, Prague, Czech Republic (P Jansa MD); Institut Clinic and Experimental Medicine, Clinic of Cardiology, Prague, Czech Republic (H Al-Hiti MD); Complexo Hospitalar Sta Casa de Porto Alegre, Porto Alegre, Brazil (G M B Meyer MD); Actelion Pharmaceuticals Ltd, Allschwil, Switzerland (E Chiossi, A Kusic-Pajic MD); and Hôpital Antoine Béclère, Université Paris-Sud, Clamart, France (Prof G Simonneau MD) Correspondence to: Prof N Galiè, Institute of Cardiology, University of Bologna, Via Massarenti 9, 40138-Bologna, Italy nazzareno.galie@unibo.it