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Long-term Ambrisentan Therapy Provides Sustained Benefit in Patients with Pulmonary Arterial Hypertension

Ronald Oudiz


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Conference: 2008 International PHA Conference and Scientific Sessions

Release Date: 06.20.2008

Presentation Type: Abstracts

Oudiz R.J., on behalf of the ARIES Study Group

Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA

BACKGROUND: Ambrisentan is an endothelin receptor type-A (ETA) selective antagonist that is approved for the treatment of pulmonary arterial hypertension (PAH) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening. Ambrisentan has been shown to improve 6-minute walk distance (6MWD; range: +31 to +59 meters [m]) and other clinical measures in two 12-week placebo-controlled studies (ARIES-1 and ARIES-2). ARIES-E is an ongoing, long‑term extension study of ARIES-1 and ARIES-2.
METHODS: This is an integrated long-term analysis of 383 PAH patients who received at least 1 dose of ambrisentan (2.5, 5, or 10 mg qd) in ARIES-1, ARIES-2, or ARIES-E. Patients who received placebo in ARIES-1 or ARIES-2 were randomized to ambrisentan in ARIES-E. Baseline was defined as the time of randomization to the first dose of ambrisentan. Data from both observed case (OC) and last observation carried forward (LOCF) analyses are presented for efficacy parameters. Dose adjustments were allowed after 24 weeks of treatment in ARIES-E; therefore, these long-term data are presented for all ambrisentan doses combined.

RESULTS: Baseline characteristics: 63% idiopathic PAH, 37% associated PAH; 46% WHO class I/II, 54% WHO class III/IV; baseline 6MWD was 347 ± 85 m. At data cut-off (November 2006), 298 subjects had received ambrisentan for at least 48 weeks. Nearly all patients with 24 or 48 weeks of exposure were receiving ambrisentan monotherapy (99% and 94%, respectively). 

6MWD and BDI Mean Change (95% CI) from Baseline

 

Week 12

Week 48

6MWD, m

N

 

N

 

      OC

360

36 (28.9, 43.0)

290

40 (30.1, 50.4)

      LOCF

375

34 (27.2, 41.1)

375

29 (19.5, 37.6)

BDI

 

 

 

 

      OC

352

-0.6 (-0.80, -0.37)

284

-0.6 (-0.85, -0.32)

      LOCF

375

-0.6 (-0.79, -0.37)

375

-0.5 (-0.69, -0.2)

* OC data is for all patients with data at Week 48; LOCF analysis includes all subjects with post-baseline data. 

In both analyses, the improvements in 6MWD and Borg dyspnea index (BDI) observed at Week 12 were maintained through Week 48. The percentage of subjects who improved or maintained WHO functional class at Week 12 (OC: 96%; LOCF: 94%) was also maintained through Week 48 (OC: 95%; LOCF: 90%). The one‑year survival estimate for subjects receiving ambrisentan was 95%. The most frequent adverse events during the first year of ambrisentan use were similar to those observed in the 12-week placebo-controlled studies and the 1-year incidence of aminotransferases >3xULN with ambrisentan use was comparable to the 12-week incidence for patients receiving placebo in ARIES‑1 and ARIES-2.

CONCLUSIONS: Ambrisentan monotherapy had sustained benefits on 6MWD, dyspnea, and WHO functional class for at least 1 year of treatment in PAH patients. Ambrisentan was well tolerated with long-term exposure and the incidence and severity of aminotransferase abnormalities remained low.