Ambrisentan in Pulmonary Arterial Hypertension Efficacy Study 1 and 2 - ARIES 1 and 2


The goal of the two trials was to evaluate the safety and efficacy of ambrisentan in patients with pulmonary arterial hypertension (PAH).


Ambrisentan is efficacious compared with placebo in improving 6-minute walk distance at 12 weeks in patients with PAH, with a good safety profile.

Study Design

Study Design:

Patients Screened: 484
Patients Enrolled: 393
Mean Follow Up: 12 weeks for all, 11 months for subset
Mean Patient Age: 50.5 years
Female: 79

Patient Populations:

Presence of PAH (idiopathic or associated with connective tissue disease, HIV infection, or anorexigen use)


• Concomitant use of bosentan, sitaxsentan, sildenafil, epoprostenol, iloprost, or treprostinil
• 6-minute walk distance <150 or >450 minutes

Primary Endpoints:

Change from baseline to week 12 in exercise capacity, as measured by the 6-minute walk distance

Secondary Endpoints:

• Time to clinical worsening
• Change in WHO functional classification of PAH
• Change in Short Form-36 Health Survey
• Change in Borg dyspnea score
• Change in plasma B-type natriuretic peptide concentration

Drug/Procedures Used:

In ARIES-1, patients were randomized in a 1:1:1 ratio to either placebo, or ambrisentan 5 or 10 mg by mouth daily, whereas in ARIES-2, patients were randomized to either placebo or ambrisentan 2.5 or 5 mg by mouth daily.

Concomitant Medications:

Treatment with bosentan, sitaxsentan, sildenafil, epoprostenol, iloprost, or treprostinil was not allowed during the 12-week duration of the trial. Of the 361 patients enrolled in the long-term study, 18 of the 298 patients receiving ambrisentan (6.0%) also needed prostanoids or phosphodiesterase type 5 inhibitors. Other medical therapy details are not available.

Principal Findings:

ARIES-1 (201 patients) was conducted in North America, whereas ARIES-2 (192 patients) was conducted in Europe. Idiopathic PAH was present in about 64% of the patients. World Health Organization (WHO) functional classification at baseline was predominantly class II (38%) or class III (55%). The mean baseline 6-minute walk distance in the six groups ranged from about 340 to 355 minutes. The mean cardiac index was 2.5 L/min/m2. The mean pulmonary vascular resistance was 885.8 dynes-sec/cm5. Other baseline characteristics were similar between the placebo and treatment arms.

Efficacy: Ambrisentan was associated with a significant improvement in the 6-minute walk distance by week 12 in both trials. The mean placebo-corrected treatment effects at week 12 were 31 minutes (95% confidence interval [CI], 3-59; p = 0.008) for ambrisentan 5 mg, and 51 minutes (95% CI, 27-76; p < 0.001) for ambrisentan 10 mg in ARIES-1, and 32 minutes (95% CI, 2-63; p = 0.022) for ambrisentan 2.5 mg, and 59 minutes (95% CI, 30-89; p = 0.001) for ambrisentan 5 mg in ARIES-2. This effect seemed to be more prominent in patients with idiopathic PAH (range 50-66 minutes), compared with PAH from other causes (range 15-23 minutes).

In ARIES-1, ambrisentan in either dose (4%) was not associated with a significant improvement in time to clinical worsening compared with placebo (9%) (p = NS). However, in ARIES-2, there was a significant difference in the time to clinical worsening between placebo (22%), and both the 2.5 mg ambrisentan arm (5%, p = 0.005) and the 5 mg ambrisentan arm (5%, p = 0.008). In ARIES-1, ambrisentan was associated with a significant improvement in the distribution of WHO functional class compared with placebo (p = 0.04); however, this was not noted in ARIES-2 (p = 0.12). Significant improvements in quality of life and the Borg dyspnea scale were noted with ambrisentan compared with placebo in both trials.

About 361 patients were enrolled in the long-term extension study, of which 298 patients received ambrisentan for at least 48 weeks. There was still a significant improvement in the 6-minute walk distance at 48 weeks in these patients: 39 minutes (95% CI, 29-49).

Safety: Most of the adverse events related to ambrisentan were mild, including peripheral edema, nasal congestion, and abdominal pain, which seemed to have a dose-related response. None of the patients in the ambrisentan arms developed significant transaminitis (>3 x upper limit of normal), compared with 2.3% of the patients in the placebo arms. No meaningful changes were noted in prothrombin time, international normalized ratio, or weekly oral anticoagulant dose in the ambrisentan-treated groups. Serious adverse events were noted in 16.7% of the patients in the placebo arms, compared with 9.6% in the ambrisentan arms. Mortality was similar between the ambrisentan (1.5%) and placebo (4.5%) arms (p = NS). Hospitalizations for PAH were similar between the groups, although the placebo group in ARIES-2 (14%) had more frequent hospitalizations compared with the placebo group in ARIES-1 (3%).


The results of ARIES-1 and -2 indicate that ambrisentan, a novel A-selective endothelin receptor antagonist, is safe and efficacious in improving clinical outcomes in patients with PAH, especially those with idiopathic PAH. This seemed to be a dose-related response, with the 10 mg arm benefiting the most, although some of the milder side effects seemed to be more frequent at higher doses as well. Further studies are needed to evaluate its long-term safety and efficacy, since they were presented for a selected subset only. Moreover, direct comparison of ambrisentan to currently used endothelin receptor antagonists such as bosentan and sitaxsentan, not only for safety and efficacy, but also for cost-effectiveness, is necessary.


Galiè N, Olschewski H, Oudiz RJ, et al.; on behalf of the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group. Ambrisentan for the Treatment of Pulmonary Arterial Hypertension. Results of the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy (ARIES) Study 1 and 2. Circulation 2008;117:3010-9.

Keywords: Connective Tissue Diseases, North America, Thiophenes, Edema, Europe, Dyspnea, HIV Infections, Pyridazines, Isoxazoles, Receptors, Endothelin, Prothrombin Time, Abdominal Pain, Quality of Life, Hypertension, Pulmonary, Heart Failure, Vascular Resistance, Hospitalization, Phenylpropionates, Sulfonamides

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