Bosentan reduces decline of patients with early stage pulmonary arterial hypertension (early study)

June 19, 2008

Patients in the early stages of pulmonary arterial hypertension (PAH) treated with the drug bosentan show reduced clinical decline compared with patients given placebo, and thus the drug could be beneficial in this group of patients. These are the conclusions of authors of an Article published in this week's edition of The Lancet.

PAH is a devastating, progressive disease with increasingly debilitating symptoms. The idiopathic form of the condition (ie, with no underlying cause) affects mainly young women but it can be associated with many other diseases in patients of both sexes and all ages. The resulting increased pulmonary vascular resistance in the lungs leads to structural damage to the heart, limiting patients' exercise capacity, and eventually, leads to heart failure and death. The protein endothelin plays a key role in PAH by binding to two receptor sites in the vascular smooth muscle cells in the lungs -- the endothelin A and B receptors. Bosentan is an orally active dual endothelin receptor antagonist, which means it competes with endothelin at both A and B receptor sites. Studies have shown that bosentan improves exercise capacity and pulmonary vascular resistance (PVR), and slows clinical decline; but these studies have focused mainly on patients with the later stages of the disease, ie, WHO functional classes III and IV. Professor Nazzareno Galiè, Institute of Cardiology, University of Bologna, Italy, and colleagues did a randomised controlled trial to assess the effects of bosentan on patients with earlier stage PAH, ie, WHO functional class II.

The trial enrolled 185 PAH patients aged 12 years or over with PAH, of whom 93 were randomised to received bosentan and 92 to placebo. The PVR of each patient was measured by right heart catheterisation*, and also the distance walked in six minutes at the start of the trial. Measurements were taken at the start of the trial (baseline) and at six months. Analyses were done with 168 patients: 80 bosentan, 88 placebo for PVR; and 177 (86 bosentan, 91 placebo) for 6 minute walk distance.

The researchers found that after six months, the mean PVR was 83.2% of baseline in the bosentan group and 107.5% in the placebo group --giving a statistically significant treatment effect of -22.6% for the bosentan patients. Mean 6 minute walk distance increased 11.2m in the bosentan group from 438m at baseline to 449m, while in the placebo group the walk distance decreased from 431m at baseline to 423m; however, the changes in walk distance were not statistically significant. Fewer bosentan-treated patients (3%) experienced clinical worsening events (death, hospitalisation, and symptomatic progression of PAH) than in the placebo group (14%) -- this finding was statistically significant. A total of 12 (13%) patients in the bosentan group and eight (9%) in the placebo group reported serious adverse events, the most common of which were fainting in the bosentan group and right ventricular failure in the placebo group.

The authors conclude: "The EARLY study shows that, if left untreated, mildly symptomatic pulmonary arterial hypertension can progressively deteriorate both clinically and in terms of pulmonary vascular resistance, despite the maintenance of exercise capacity. Bosentan treatment in this patient population is associated with improvements in pulmonary vascular resistance and prevention of clinical deterioration. These findings indicate that treatment with bosentan might be of benefit to patients with WHO FC II pulmonary arterial hypertension."

In an accompanying Comment, Dr Neeraj Dhaun and Professor David Webb, Queen's Medical Research Institute, University of Edinburgh, UK, say: "This study broadens the potential for bosentan as a treatment in pulmonary arterial hypertension, and the evidence presented by Galiè and colleagues should soon be translated into clinical practice. The scope of endothelin-receptor antagonism as a treatment option continues to extend beyond pulmonary arterial hypertension and includes chronic kidney disease, diastolic heart failure, resistant hypertension, and cancer."
-end-
Notes to editors: *right heart catheterisation: the insertion of a small catheter through a peripheral vein into the pulmonary artery.

Professor Nazzareno Galiè, Institute of Cardiology, University of Bologna, Italy T) +39-338-6721805 E) nazzareno.galie@unibo.it

Dr Neeraj Dhaun and Professor David Webb, Queen's Medical Research Institute, University of Edinburgh, UK T) + 44 (0) 131 242 9210 E) bean.dhaun@ed.ac.uk

http://multimedia.thelancet.com/pdf/press/pulmonaryarteryhypertension.pdf

Lancet

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