Abstract #2166: Ambrisentan Therapy for Pulmonary Arterial Hypertension Associated with Connective Tissue Diseases
Authors:
David Badesch, on behalf of the ARIES Study Group
Background
This study examined the subset of subjects with connective tissue disease (CTD)-associated pulmonary arterial hypertension (PAH) treated with ambrisentan, a selective endothelin A receptor antagonist.
Methods:
This study pooled the data from the 2 randomized controlled trials, ARIES-1 and ARIES-2 and included approximately 32% patients with CTD-associated PAH. ARIES-1 examined 5 and 10 mg doses of ambrisentan compared to placebo and ARIES-1 examined 2.5 and 5 mg doses compared to placebo in 12 week treatment trials. 124 of the 374 subjects in these trials had CTD (35% with CREST, 26% with diffuse scleroderma, 15% with systemic lupus and 20% with mixed connective tissue disease, 4% overlap connective tissue disease). 44% had WHO class II symptoms and 53% WHO Class III. The main outcome measure in both trials was change in six minute walk test (6MWT).
Results:
When all treatment dose groups were combined (2.5, 5 and 10 mg) and compared to placebo there was a placebo-adjusted improvement of 19 meters in the treatment group (p=0.056) and 25 meters when the 5 and 10 mg groups were combined (p=0.02). There was also a trend toward benefit in functional class with some evidence of dose response. At week 12, 10.5% of the subjects treated with 2.5mg, 2.5% with 5 mg and 0% with 10 mg had WHO functional class deterioration compared to 20.9% of those treated with placebo. There were no differences noted in time to clinical worsening. There were no significant adverse events, specifically no significant increase in liver function tests. There were more cases of peripheral edema in treated patients compared to placebo.
Editorial Comment:
Multiple studies have shown that patients with CTD-associated PAH do worse than those with other forms of PAH and there has been some data to show that they may not be as responsive to PAH therapy. This study is reassuring that patients with CTD-associated PAH seem to have some benefit, although not of the same magnitude of the overall study population. In ARIES-1 the overall increase in 6MWT was 23 and 44 meters in the 5 and 10 mg groups respectively compared to -8 meters in placebo (31 and 52 placebo adjusted improvement). In ARIES-2 the overall increases were 22 and 49 meters in the 2.5 and 5 mg groups compared to -10 meters in placebo (32 and 59 placebo adjusted improvement). There was no subset analysis of the patients with scleroderma. This study did include patients with systemic lupus, who may have a different pathophysiology behind their PAH and may be more responsive to treatment in theory which potentially could skew the CTD data.
