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Endothelin Antagonist Trial in Mildly Symptomatic Pulmonary Arterial Hypertension Patients - EARLY
Description:
The goal of this trial was to assess the efficacy of bosentan in patients with mildly symptomatic pulmonary arterial hypertension (PAH) (World Health Organization [WHO] functional class [FC] II). Most clinical trials on the use of these agents have been conducted primarily in patients with WHO FC III and IV symptoms.
Hypothesis:
Bosentan is efficacious compared with placebo in reducing resting pulmonary vascular resistance (PVR) and in improving 6-minute walk distance at 6 months in patients with PAH.
Study Design
Study Design:
Patients Screened: 476
Patients Enrolled: 185
Mean Follow Up: 6 months
Mean Patient Age: 44.7 years
Female: 70
Patient Populations:
• Age >12 years
• WHO FC II PAH (idiopathic, familial, or associated with atrial septal defect of <2 cm in diameter, ventricular septal defect <1 cm in diameter, patent ductus arteriosus, connective tissue or autoimmune diseases, HIV infection, or anorexigen use)
• Baseline 6-minute walk distance of <80% of the normal predicted value or <500 m in combination with a Borg dyspnea index of 2 points or more, and pulmonary vascular resistance of ≥320 dynes/sec/cm5.
Exclusions:
• Concomitant use of prostanoids and other endothelin receptor antagonist drugs
Primary Endpoints:
• % change from baseline to 6 months in PVR at rest
• Change from baseline to 6 months in 6-minute walk distance
Secondary Endpoints:
• Time to clinical worsening
• Change in WHO functional classification of PAH
• Change in Borg dyspnea score
• Change in total pulmonary resistance, mean arterial pressure, cardiac index, and mixed venous oxygen saturation
Drug/Procedures Used:
Patients were randomized to either placebo or bosentan at an initial dose of 62.5 mg twice daily, with up-titration to 125 mg twice daily after 4 weeks (unless weight <40 kg).
Concomitant Medications:
Sildenafil (15.5%), calcium channel blockers (36%), and oral anticoagulation (62.5%). Treatment with prostanoids and other endothelin receptor antagonist drugs was not permitted during the trial.
Principal Findings:
EARLY was conducted in 52 sites in 21 countries. Idiopathic PAH was present in about 60.5% of the patients. The mean time from diagnosis was 3.3 years. The mean baseline 6-minute walk distance was about 434.5 m. The mean cardiac index was 2.7 L/min/m2. The mean PVR was 822 dynes/sec/cm5. Other baseline characteristics were similar between the placebo and treatment arms, except there were more women in the bosentan arm compared with placebo.
The primary analysis for PVR was conducted in 168 patients. At month 6, the mean PVR was significantly improved in the bosentan arm: 83.2% (95% confidence interval [CI] 73.8-93.7) of the baseline value in the bosentan group compared with 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). Effects were similar with or without the concomitant use of sildenafil. The primary analysis for 6-minute walk distance was conducted in 177 patients. Mean 6-minute walk distance increased in the bosentan group (11.2 m, 95% CI -4.6 to 27.0) and decreased in the placebo group (-7.9 m, 95% CI -24.3 to 8.5). However, this treatment effect was not statistically significant (p = 0.08). Treatment effects were similar in patients with idiopathic PAH compared with other causes.
Bosentan was associated with a significant delay in clinical worsening compared with placebo (hazard ratio 0.23, 95% CI 0.065-0.80, p = 0.01). Moreover, clinical worsening was noted in fewer patients in the bosentan group compared with placebo (3% vs. 14%), primarily due to a reduction in the symptomatic progression of PAH (1% vs. 10%); mortality was similar (1%). FC worsening was also lower in the bosentan group (3.4% vs. 13.2%, p = 0.03). Hemodynamic parameters also seemed to improve with bosentan, including pulmonary arterial pressure (5.7 mm Hg, p < 0.0001), cardiac index (0.24 L/min/m2, p = 0.03), and mixed venous saturation (4.8%, p = 0.002).
Overall, the incidence of side effects was similar between bosentan and placebo (70% vs. 65%). The most common side effects with bosentan included nasopharyngitis (8% vs.9%) and abnormal liver-associated enzymes (8% vs. 3%). Significant transaminitis (>3 x upper limit of normal) was more common with bosentan (13% vs. 2%).
A total of 157 patients (77 from the bosentan group and 80 from the placebo group) were included in the open-label extension study, in which all patients from both groups were given bosentan treatment. Over a median follow-up of 19.5 months, seven experienced serious treatment-related side effects.
Interpretation:
The results of EARLY indicate that bosentan, an endothelin A and B receptor antagonist, is associated with an improvement in 6-minute walk distance and a reduction in PVR in patients with WHO FC II PAH at 6 months. Most clinical trials had included only a small population of patients with WHO FC II. Early treatment may thus help to offset or at least delay the development of some of the downstream complications from PAH.
Given that many patients with FC II PAH will need to stay on bosentan for periods longer than 6 months, long-term data are necessary before widespread implementation. Moreover, comparison of safety, efficacy, and cost-effectiveness of bosentan to the other endothelin receptor antagonists, such as ambrisentan and sitaxsentan is necessary, as is the systematic evaluation of the role of combination therapy of endothelin receptor antagonists with other agents such as prostanoids and sildenafil.
References:
Galie N, Rubin LJ, Hoeper MM, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet 2008;371:2093-100.
Keywords: Thromboembolism, Stroke, Myocardial Ischemia, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Warfarin, Blood Pressure
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