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Investigative Ambrisentan Treatment Appears to Help People With Pulmonary Arterial Hypertension (PAH): Presented at CHEST
Treatment with the investigative oral agent ambrisentan appear to be helpful for patients with pulmonary arterial hypertension (PAH), researchers reported at CHEST 2006, the annual meeting of the American College of Chest Physicians. Patients were able to achieve the primary endpoint -- increased distance in the 6-minute walk test compared with placebo -- in the Ambrisentan in PAH - A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study of Ambrisentan in Subjects with Pulmonary Arterial Hypertension (ARIES I). In ARIES, Lewis Rubin, MD, professor of medicine and director, pulmonary hypertension program, University of California, San Diego, California, said that placebo patients had a small decline in their 6-minute walk of 7.8 m after 12 weeks, while patients on the 5 mg daily dose of ambrisentan had a 30.6 m average increase ([P = .0084) and patients on 10 mg of ambrisentan achieved an average of 51.4 m increase (P = .0001).
In addition to improving endurance, patients on the drug also reduced levels of brain natriuretic peptide -- a marker of PAH severity. "This is the first trial to show that an oral medication can reduce levels of brain natriuretic peptide," said Dr. Rubin in his oral presentation on October 24th.
After 12 weeks the level has increased by 11.8 pg/mL in placebo patients but decreased by 62.5 pg/mL in patients on the 5 mg dose (P = .002) and decreased by 149.3 pg/mL in patients on the 10 mg dose (P = .0001), he said.
Dr. Rubin and colleagues enrolled 202 patients in the 3-arm trial, with 67 patients assigned to placebo, 67 to 5 mg daily of ambrisentan and 68 patients to ambrisentan 5 mg daily. Ten patients dropped out of the placebo group; 4 subjects left the 5 mg group and 5 patients left the 10 mg group before the end of the study. Once daily dosing is used with ambrisentan because the drug has a 15-hour half life, Dr. Rubin said.
Ambrisentan is an endothelin selective receptor antagonist being developed as an oral therapy for patients with pulmonary arterial hypertension. Endothelin is a small peptide hormone that is believed to play a critical role in the control of blood flow and cell growth. Elevated endothelin blood levels are associated with several cardiovascular diseases, including PAH, chronic kidney disease, hypertension, chronic heart failure, stroke and restenosis of arteries after balloon angioplasty or stent implantation.
In the double-blind, placebo-controlled 12-week trial, patients were treated either with placebo or ambrisentan 5 mg for 2 weeks. After 2 weeks, half the patients on ambrisentan were titrated to 10 mg and remained on that dosage through the end of the trial, Dr. Rubin said.
The study was open to adults diagnosed with PAH and their disease severity was measured using several lung function tests, including the 6-minute walk distance. They were required to walk between 150 and 450 m. The primary endpoint of the study was the change in distance covered in the 6-minute walk.
About 84% of study subjects were women, who are disproportionately affected by PAH. The average age was 50 years. About two-thirds of patients had idiopathic PAH.
The study was sponsored by Myogen, Westminster, Colorado.
[Presentation title: ARIES-1: A Placebo-Controlled, Efficacy and Safety Study of Ambrisentan in Patients With Pulmonary Arterial Hypertension. Abstract 4517]
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