Christopher Dufton

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

Background— Ambrisentan is a propanoic acid–based, A-selective endothelin receptor antagonist for the once-daily treatment of pulmonary arterial hypertension. Methods and Results— Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study 1 and 2 (ARIES-1 and ARIES-2) were concurrent, double-blind, placebo-controlled studies that randomized 202 and 192 patients with pulmonary arterial hypertension, respectively, to placebo or ambrisentan (ARIES-1, 5 or 10 mg; ARIES-2, 2.5 or 5 mg) orally once daily for 12 weeks. The primary end point for each study was change in 6-minute walk distance from baseline to week 12. Clinical worsening, World Health Organization functional class, Short Form-36 Health Survey score, Borg dyspnea score, and B-type natriuretic peptide plasma concentrations also were assessed. In addition, a long-term extension study was performed. The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 m (P=0.008) and 51 m (P<0.001) in ARIES-1 for 5 and 10 mg ambrisentan, respectively, and 32 m (P=0.022) and 59 m (P<0.001) in ARIES-2 for 2.5 and 5 mg ambrisentan, respectively. Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed. No patient treated with ambrisentan developed aminotransferase concentrations >3 times the upper limit of normal. In 280 patients completing 48 weeks of treatment with ambrisentan monotherapy, the improvement from baseline in 6-minute walk at 48 weeks was 39 m. Conclusions— Ambrisentan improves exercise capacity in patients with pulmonary arterial hypertension. Improvements were observed for several secondary end points in each of the studies, although statistical significance was more variable. Ambrisentan is well tolerated and is associated with a low risk of aminotransferase abnormalities.

Long-Term Ambrisentan Therapy for the Treatment of Pulmonary Arterial Hypertension

OBJECTIVES This study evaluated the safety and efficacy of ambrisentan for a period of 2 years in patients with pulmonary arterial hypertension (PAH). BACKGROUND Ambrisentan is an oral, once-daily endothelin receptor antagonist that is selective for the endothelin type A receptor. The ARIES-1 (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies) and ARIES-2 trials were the pivotal 12-week, placebo-controlled studies that led to the regulatory approval of ambrisentan (5 and 10 mg) for the treatment of PAH. METHODS In the ARIES-1 and -2 studies, and the subsequent long-term extension protocol, the ARIES-E study, 383 patients received ambrisentan (2.5, 5, or 10 mg). Efficacy and safety assessments are presented from the time of the first dose of ambrisentan for all patients with post-baseline data. RESULTS After 2 years of ambrisentan exposure, the mean change from baseline in 6-min walk distance was improved for the 5-mg (+23 m; 95% confidence interval: 9 to 38 m) and 10-mg (+28 m; 95% confidence interval: 11 to 45 m) groups. Estimates of survival and freedom from clinical worsening for the combined dose group were 94% and 83%, respectively, at 1 year and 88% and 72%, respectively, at 2 years. The annualized risk of aminotransferase abnormalities >3x the upper limit of normal was approximately 2% per year; most of these events were mild and did not lead to discontinuation of drug. CONCLUSIONS Two years of ambrisentan treatment was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period. (A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 or AMB-321; NCT00578786).

ARIES-3: ambrisentan therapy in a diverse population of patients with pulmonary hypertension.

INTRODUCTION Ambrisentan is an oral, once daily, endothelin receptor antagonist approved for treatment of pulmonary arterial hypertension (PAH). Previous studies of ambrisentan were limited to patients with Group 1 PAH and often excluded patients receiving other pulmonary hypertension (PH) therapies. AIMS ARIES-3 was an open-label study evaluating efficacy and safety of ambrisentan in patients with various PH etiologies and background PH medications. Patients received 5 mg ambrisentan once daily for 24 weeks. The primary endpoint was change from baseline in 6-minute walk distance (6MWD) at week 24. RESULTS A total of 224 patients with PH due to idiopathic and familial PAH (31%), connective tissue disease (18%), chronic hypoxemia (22%), chronic thromboembolic disease (13%), or other etiologies (16%) were enrolled and 53% of patients received stable background PAH therapies. After 24 weeks of therapy, an increase in 6MWD (+21 m; 95% CI: 12-29) and a decrease in B-type natriuretic peptide (-26%; 95% CI: -34 to -16%) was observed in the overall population compared to baseline; however, increases in 6MWD were not observed in several non-Group 1 PH subpopulations. Peripheral edema, headache, and dyspnea were the most common adverse events. CONCLUSION This study reconfirms the results of previous placebo-controlled studies, which demonstrate that ambrisentan is well tolerated and provides benefit in patients with PAH. Definitive conclusions regarding the safety and efficacy of ambrisentan in specific non-Group 1 PH etiologies cannot be determined and larger, controlled studies will be necessary to determine the efficacy and safety of ambrisentan in these populations.

Baseline and follow-up 6-min walk distance and brain natriuretic peptide predict 2-year mortality in pulmonary arterial hypertension.

BACKGROUND Six-minute walk distance (6MWD) and brain natriuretic peptide (BNP) levels at baseline and after initiation of treatment have been associated with survival in patients with pulmonary arterial hypertension. Our objective was to determine the individual and additive ability of pretreatment and posttreatment 6MWD and BNP to discriminate 2-year survival in patients with pulmonary arterial hypertension. METHODS We included patients enrolled in two randomized clinical trials of ambrisentan who had 2-year follow-up (N 5 370). 6MWD and BNP were assessed before and after 12 weeks of treatment. Receiver operating characteristic curve analyses were performed to identify optimal cutoffs that defi ned subgroups with a high 2-year mortality. Classifi cation and regression tree analysis was used to determine the incremental prognostic value of combined assessments. RESULTS 6MWD at baseline and after 12 weeks of therapy were similarly discriminatory of 2-year survival (c-statistics 5 0.77 [95% CI 0.70-0.84] and 0.82 [95% CI 0.75-0.88], respectively), whereas change in 6MWD from baseline to week 12 was not discriminating. The same observation was true of BNP at baseline and after 12 weeks of therapy (c-statistics 5 0.68 [95% CI 0.60-0.76] and 0.74 [95% CI 0.66-0.82], respectively). After consideration of baseline 6MWD, there was no prognostic information added by the week 12 6MWD or BNP at either time point. CONCLUSIONS 6MWD and BNP values at baseline or week 12 identifi ed a population with an elevated risk of death at 2 years. A repeat assessment of 6MWD or BNP after 12 weeks of ambrisentan therapy did not provide additional prognostic information beyond that obtained from baseline values.

Compelling Evidence of Long-Term Outcomes in Pulmonary Arterial Hypertension?: A Clinical Perspective

Pulmonary arterial hypertension (PAH) is a rare and progressive disease of the pulmonary arterial circulation that is characterized by a progressive rise in pulmonary vascular resistance, eventually leading to right-heart failure and death. There are currently 3 classes of drugs approved for the treatment of PAH: prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. All of these therapies have been approved for use on the basis of relatively small, short-term studies, yet it is common for each to be administered (alone or in combination) over the lifetime of a patient with PAH. Very few prospective, well-controlled PAH studies have examined long-term clinical outcomes associated with current medical therapy. Therefore, data that support the long-term therapeutic benefits of these long-term PAH therapies are limited and derived primarily from uncontrolled, observational studies. In this perspective, the authors review the published research to assess the strengths and weaknesses of the data that support the long-term clinical benefit of current PAH therapies. The authors conclude that current medical therapies approved for the treatment of PAH can provide sustained benefits in hemodynamic function and exercise capacity. The cumulative evidence, in the form of meta-analysis and registry data, suggest that patients are living longer compared with untreated patients; the reasons are likely multifactorial. Although definitive evidence will require randomized and properly controlled long-term trials, the current evidence supports the long-term use of these drugs for the treatment of patients with PAH.

Long-Term Pulmonary Hemodynamic Effects of Ambrisentan in Pulmonary Arterial Hypertension

The long-term effects of endothelin receptor antagonists on pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) are not well studied. This post hoc analysis examined changes in pulmonary hemodynamics in a cohort of patients with PAH who underwent follow-up right heart catheterization (RHC) in a long-term ambrisentan study (ARIES-E). A retrospective review was conducted of patients who underwent RHC after >3 months of ambrisentan therapy. Changes from baseline in mean PAP, mean right atrial pressure, cardiac index, and PVR were assessed and correlations between these hemodynamic changes and exercise capacity were examined. Sixty-eight patients who received ambrisentan in the ARIES studies had ≥1 follow-up RHC while receiving ambrisentan. Fifty-eight patients were on ambrisentan alone at the time of the first RHC. Median time from initiation of ambrisentan therapy to follow-up RHC was 60 weeks (range 14 to 158). Significant improvements compared to baseline were observed for mean PAP (-7.6 mm Hg, 95% confidence interval [CI] -10.0 to -5.1), PVR (-266 dyne × s/cm(5), 95% CI -350 to -180), and cardiac index (0.4 L/min/m(2), 95% CI 0.2 to 0.6 L/min/m(2)); for patients on ambrisentan alone, changes in mean PAP and PVR were inversely correlated with change from baseline 6-minute walking distance (r = -0.41 and -0.43, respectively, p <0.001 for the 2 comparisons) at time of follow-up RHC. In conclusion, ambrisentan may provide sustained improvements in pulmonary hemodynamics in patients with PAH who receive long-term treatment and these changes correlate with improvements in exercise capacity.

Ambrisentan for pulmonary arterial hypertension.

Endothelin receptor antagonists (ERAs) are an important class of agents used for the treatment of pulmonary arterial hypertension (PAH). Ambrisentan is an oral, once-daily, endothelin type-A receptor (ETA)-selective, propanoic acid class ERA under clinical investigation for the treatment of PAH. In a Phase II study, ambrisentan improved 6-minute walk distance, Borg dyspnea index, World Health Organization Functional Class, and hemodynamics. Ambrisentan was well tolerated and adverse events were not dose related, including a low incidence and severity of liver function test abnormalities. There are no relevant interactions between ambrisentan and cytochrome P450 isoenzymes (metabolism, induction or inhibition) that might alter the activity of P450-metabolized drugs. Potential benefits of ambrisentan include oral, once-daily dosing, ET(A)-receptor selectivity, and the decreased risks of liver toxicity and adverse drug-drug interactions compared with other ERAs.