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Ambrisentan Therapy in Patients with Chronic Thromboembolic Disease: An Analysis from the ARIES-3 Study

Lewis Rubin

H. Gillies

M. Allard

C. Blair

David Badesch


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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

Rubin LJ1; Gillies H2; Allard M2; Blair C2; Badesch DB3 on behalf of the ARIES-3 Study Group.

1. University of California San Diego, La Jolla, CA, USA
2. Gilead Sciences Inc., Foster City, CA, USA
3. University of Colorado, Denver, CO, USA

BACKGROUNDAmbrisentan (ABS) is an ETA-selective endothelin receptor antagonist approved for the treatment of Group 1 pulmonary arterial hypertension (PAH). The therapeutic effects of ABS in Group1 PAH patients have been well described. ARIES-3 is an open-label study that evaluated efficacy and safety of ABS in a diverse pulmonary hypertension patient population.

METHODS224 patients with pulmonary hypertension (Groups 1, 3, 4, and 5) received 48-weeks of ABS therapy (5 mg once-daily x 24 weeks, then the dose could be increased to 10 mg once-daily) in the ARIES-3 study. This exploratory post-hoc subgroup analysis examines in detail for the first time the response to ABS of Group 4 Chronic Thromboembolic Pulmonary Hypertension (CTEPH) patients compared with Group 1 PAH patients. Change from baseline through week 48 is presented using last observation carried forward imputation for missing data.

RESULTS29 patients had CTEPH (proximal, n=11; distal, n=18) and 139 patients had PAH. CTEPH patients were older (6316 years) than PAH patients (5015 years). Baseline characteristics were similar between subgroups. At 48 weeks, improvements in 6-minute walk distance (6MWD) were +19 m (95% CI: 0.2 to 37) in the CTEPH subgroup and +36 m (95% CI: 25 to 48) in the PAH subgroup. The decrease in B-type natriuretic peptide (BNP) was -22% (95% CI: -41% to +3%) in the CTEPH subgroup compared to -20% (95% CI: -32% to -6%) in the PAH subgroup. Improvements from baseline in Borg Dyspnea Index scores were -0.8% (95% CI: -1.2% to +0.3%) in the CTEPH subgroup compared to -0.7% (95% CI: -1.0% to -0.3%) in the PAH subgroup. Approximately 90% of patients improved or maintained their WHO functional class at week 48Kaplan-Meier estimates of survival were 93% (95% CI: 74% to 98%) in the CTEPH and 98% (95% CI: 93% to 99%) in the PAH subgroup at week 48. Kaplan-Meier estimates of event free clinical worsening was 86% (95% CI: 66% to 94%) in the CTEPH subgroup and 85% (95% CI: 77% to 90%) in the PAH subgroup. Adverse events reported were comparable between the 2 subgroups, with peripheral edema and headache being the most common events.

CONCLUSIONSAmbrisentan was generally well-tolerated in CTEPH patients and trends toward improvement in exercise ability and dyspnea were observed. This post-hoc analysis provides a rationale for performing larger, placebo-controlled controlled studies to determine the efficacy and safety of ambrisentan in CTEPH.