Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial

Lancet. 2008 Jun 21;371(9630):2093-100. doi: 10.1016/S0140-6736(08)60919-8.


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, 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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antihypertensive Agents / adverse effects
  • Antihypertensive Agents / therapeutic use*
  • Bosentan
  • Double-Blind Method
  • Female
  • Humans
  • Hypertension, Pulmonary / classification
  • Hypertension, Pulmonary / drug therapy*
  • Male
  • Middle Aged
  • Severity of Illness Index
  • Sulfonamides / adverse effects
  • Sulfonamides / therapeutic use*
  • Treatment Outcome
  • Vascular Resistance
  • Walking


  • Antihypertensive Agents
  • Sulfonamides
  • Bosentan

Associated data