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Gerald Simonneau - One of the best experts on this subject based on the ideXlab platform.
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initial combination therapy with Ambrisentan tadalafil on pulmonary arterial hypertension related hospitalization in the ambition trial
Journal of Heart and Lung Transplantation, 2019Co-Authors: Jeanluc Vachiery, Adaani E Frost, Vallerie V Mclaughlin, Nazzareno Galie, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Marius M Hoeper, Andrew J Peacock, Gerald SimonneauAbstract:BACKGROUND In the randomized, double-blind, event-driven AMBITION study, initial combination therapy with Ambrisentan and tadalafil was associated with a 50% reduction in risk of clinical failure (first occurrence of all-cause death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) vs pooled monotherapy. These results were primarily driven by a reduction in PAH-related hospitalization in the combination therapy group, although a significant effect was not observed in a post-hoc analysis of all-cause hospitalization. METHODS The effect of initial combination therapy with Ambrisentan and tadalafil in AMBITION was further explored to study PAH-related hospitalization, which was not reported in the primary publication. RESULTS Initial combination therapy was associated with a 63% reduction in risk of PAH-related hospitalization when compared with pooled monotherapy (hazard ratio [HR] 0.372, 95% confidence interval [CI] 0.217 to 0.639, p = 0.0002). For every 9 patients treated with combination therapy vs monotherapy, 1 PAH-related hospitalization could be prevented over a 1-year period. Serious adverse events leading to hospitalization, not necessarily PAH-related, occurred in 87 of 253 (34%) and 89 of 247 (36%) of patients on combination therapy and pooled monotherapy, respectively (post-hoc summary). CONCLUSIONS Initial combination therapy with Ambrisentan and tadalafil was found to reduce the risk of PAH-related hospitalization by 63% compared with pooled monotherapy.
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initial combination therapy with Ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension a secondary analysis of the results from the randomised controlled ambition study
The Lancet Respiratory Medicine, 2016Co-Authors: Marius M Hoeper, Adaani E Frost, Vallerie V Mclaughlin, Stephan Rosenkranz, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Andrew J Peacock, Gerald Simonneau, Ronald J OudizAbstract:Summary Background In treatment-naive patients with pulmonary arterial hypertension, initial combination therapy with Ambrisentan and tadalafil reduces the risk of clinical failure events compared with monotherapy. We did this secondary analysis to further investigate the effect of combination therapy on survival. Methods We analysed survival data from the modified intention-to-treat population of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial. AMBITION was a multicentre, randomised, double-blind study, in which treatment-naive patients with pulmonary arterial hypertension were randomly assigned in a 2:1:1 ratio and received combination therapy with Ambrisentan and tadalafil, Ambrisentan and placebo, or tadalafil and placebo. We did a prespecified analysis of all mortality events from randomisation to the end of the study, including patients who discontinued their assigned treatment. In a post-hoc analysis, we analysed survival at 7 days after the termination of each individual patient's randomised treatment. We used Cox proportional hazard regression, Kaplan-Meier survival estimates, and the stratified log-rank test to compare the survival of patients receiving initial combination therapy or initial monotherapy. Findings The study population consisted of 605 patients with pulmonary arterial hypertension who were randomly assigned and received combination therapy (n=302) or monotherapy (n=303; 152 patients assigned to Ambrisentan monotherapy and 151 patients to tadalafil monotherapy). At the end of the study, 29 (10%) of 302 patients in the combination therapy group had died compared with 41 (14%) of 303 patients in the monotherapy group (hazard ratio 0·67, 95% CI 0·42–1·08; stratified log-rank p=0·10). At 7 days after the end of randomised treatment, fewer patients had died in the combination therapy group (3 [1%] of 302 patients) compared with the monotherapy group (13 [4%] of 303 patients; hazard ratio 0·21, 95% CI 0·06–0·73). Interpretation These data indicate that initial combination therapy might be associated with a survival advantage compared with initial monotherapy in patients with newly diagnosed pulmonary arterial hypertension. This hypothesis needs to be addressed in future studies. Funding Gilead, GlaxoSmithKline.
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initial use of Ambrisentan plus tadalafil in pulmonary arterial hypertension
The New England Journal of Medicine, 2015Co-Authors: Nazzareno Galie, Adaani E Frost, Vallerie V Mclaughlin, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Marius M Hoeper, Andrew J Peacock, Gerald Simonneau, Jeanluc Vachiery, Ekkehard GrünigAbstract:The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the Ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooledmonotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro–brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, −67.2% vs. −50.4%; P<0.001), as well as a higher percentage of pa tients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P = 0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia. CONCLUSIONS Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with Ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with Ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.)
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initial combination therapy with Ambrisentan and tadalafil in connective tissue disease associated pulmonary arterial hypertension ctd pah subgroup analysis from the ambition trial
Annals of the Rheumatic Diseases, 2015Co-Authors: J G Coghlan, Adaani E Frost, Vallerie V Mclaughlin, Nazzareno Galie, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Marius M Hoeper, Andrew J Peacock, Masataka Kuwana, Gerald SimonneauAbstract:Background Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. Objective To explore the safety and efficacy of initial combination therapy with Ambrisentan and tadalafil versus Ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. Methods This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with Ambrisentan plus tadalafil or monotherapy with Ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). Results In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. Conclusions This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial Ambrisentan and tadalafil combination therapy. Trial registration number NCT01178073, post results.
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Ambrisentan therapy for pulmonary arterial hypertension
Journal of the American College of Cardiology, 2005Co-Authors: Nazzareno Galie, Adaani E Frost, David B Badesch, Michael D Mcgoon, Ronald J Oudiz, Gerald Simonneau, A Keogh, Diane Zwicke, Robert Naeije, Shelley ShapiroAbstract:OBJECTIVES The purpose of this study was to examine the efficacy and safety of four doses of Ambrisentan, an oral endothelin type A receptor-selective antagonist, in patients with pulmonary arterial hypertension (PAH). BACKGROUND Pulmonary arterial hypertension is a life-threatening and progressive disease with limited treatment options. Endothelin is a vasoconstrictor and smooth muscle cell mitogen that plays a critical role in the pathogenesis and progression of PAH. METHODS In this double-blind, dose-ranging study, 64 patients with idiopathic PAH or PAH associated with collagen vascular disease, anorexigen use, or human immunodeficiency virus infection were randomized to receive 1, 2.5, 5, or 10 mg of Ambrisentan once daily for 12 weeks followed by 12 weeks of open-label Ambrisentan. The primary end point was an improvement from baseline in 6-min walk distance (6MWD); secondary end points included Borg dyspnea index, World Health Organization (WHO) functional class, a subject global assessment, and cardiopulmonary hemodynamics. RESULTS At 12 weeks, Ambrisentan increased 6MWD (+36.1 m, p 3 times the upper limit of normal (3.1%). CONCLUSIONS Ambrisentan appears to improve exercise capacity, symptoms, and hemodynamics in patients with PAH. The incidence and severity of liver enzyme abnormalities appear to be low.
Adaani E Frost - One of the best experts on this subject based on the ideXlab platform.
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initial combination therapy with Ambrisentan tadalafil on pulmonary arterial hypertension related hospitalization in the ambition trial
Journal of Heart and Lung Transplantation, 2019Co-Authors: Jeanluc Vachiery, Adaani E Frost, Vallerie V Mclaughlin, Nazzareno Galie, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Marius M Hoeper, Andrew J Peacock, Gerald SimonneauAbstract:BACKGROUND In the randomized, double-blind, event-driven AMBITION study, initial combination therapy with Ambrisentan and tadalafil was associated with a 50% reduction in risk of clinical failure (first occurrence of all-cause death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) vs pooled monotherapy. These results were primarily driven by a reduction in PAH-related hospitalization in the combination therapy group, although a significant effect was not observed in a post-hoc analysis of all-cause hospitalization. METHODS The effect of initial combination therapy with Ambrisentan and tadalafil in AMBITION was further explored to study PAH-related hospitalization, which was not reported in the primary publication. RESULTS Initial combination therapy was associated with a 63% reduction in risk of PAH-related hospitalization when compared with pooled monotherapy (hazard ratio [HR] 0.372, 95% confidence interval [CI] 0.217 to 0.639, p = 0.0002). For every 9 patients treated with combination therapy vs monotherapy, 1 PAH-related hospitalization could be prevented over a 1-year period. Serious adverse events leading to hospitalization, not necessarily PAH-related, occurred in 87 of 253 (34%) and 89 of 247 (36%) of patients on combination therapy and pooled monotherapy, respectively (post-hoc summary). CONCLUSIONS Initial combination therapy with Ambrisentan and tadalafil was found to reduce the risk of PAH-related hospitalization by 63% compared with pooled monotherapy.
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initial combination therapy with Ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension a secondary analysis of the results from the randomised controlled ambition study
The Lancet Respiratory Medicine, 2016Co-Authors: Marius M Hoeper, Adaani E Frost, Vallerie V Mclaughlin, Stephan Rosenkranz, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Andrew J Peacock, Gerald Simonneau, Ronald J OudizAbstract:Summary Background In treatment-naive patients with pulmonary arterial hypertension, initial combination therapy with Ambrisentan and tadalafil reduces the risk of clinical failure events compared with monotherapy. We did this secondary analysis to further investigate the effect of combination therapy on survival. Methods We analysed survival data from the modified intention-to-treat population of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial. AMBITION was a multicentre, randomised, double-blind study, in which treatment-naive patients with pulmonary arterial hypertension were randomly assigned in a 2:1:1 ratio and received combination therapy with Ambrisentan and tadalafil, Ambrisentan and placebo, or tadalafil and placebo. We did a prespecified analysis of all mortality events from randomisation to the end of the study, including patients who discontinued their assigned treatment. In a post-hoc analysis, we analysed survival at 7 days after the termination of each individual patient's randomised treatment. We used Cox proportional hazard regression, Kaplan-Meier survival estimates, and the stratified log-rank test to compare the survival of patients receiving initial combination therapy or initial monotherapy. Findings The study population consisted of 605 patients with pulmonary arterial hypertension who were randomly assigned and received combination therapy (n=302) or monotherapy (n=303; 152 patients assigned to Ambrisentan monotherapy and 151 patients to tadalafil monotherapy). At the end of the study, 29 (10%) of 302 patients in the combination therapy group had died compared with 41 (14%) of 303 patients in the monotherapy group (hazard ratio 0·67, 95% CI 0·42–1·08; stratified log-rank p=0·10). At 7 days after the end of randomised treatment, fewer patients had died in the combination therapy group (3 [1%] of 302 patients) compared with the monotherapy group (13 [4%] of 303 patients; hazard ratio 0·21, 95% CI 0·06–0·73). Interpretation These data indicate that initial combination therapy might be associated with a survival advantage compared with initial monotherapy in patients with newly diagnosed pulmonary arterial hypertension. This hypothesis needs to be addressed in future studies. Funding Gilead, GlaxoSmithKline.
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initial use of Ambrisentan plus tadalafil in pulmonary arterial hypertension
The New England Journal of Medicine, 2015Co-Authors: Nazzareno Galie, Adaani E Frost, Vallerie V Mclaughlin, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Marius M Hoeper, Andrew J Peacock, Gerald Simonneau, Jeanluc Vachiery, Ekkehard GrünigAbstract:The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the Ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooledmonotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro–brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, −67.2% vs. −50.4%; P<0.001), as well as a higher percentage of pa tients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P = 0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia. CONCLUSIONS Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with Ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with Ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.)
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initial combination therapy with Ambrisentan and tadalafil in connective tissue disease associated pulmonary arterial hypertension ctd pah subgroup analysis from the ambition trial
Annals of the Rheumatic Diseases, 2015Co-Authors: J G Coghlan, Adaani E Frost, Vallerie V Mclaughlin, Nazzareno Galie, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Marius M Hoeper, Andrew J Peacock, Masataka Kuwana, Gerald SimonneauAbstract:Background Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. Objective To explore the safety and efficacy of initial combination therapy with Ambrisentan and tadalafil versus Ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. Methods This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with Ambrisentan plus tadalafil or monotherapy with Ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). Results In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. Conclusions This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial Ambrisentan and tadalafil combination therapy. Trial registration number NCT01178073, post results.
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aries 3 Ambrisentan therapy in a diverse population of patients with pulmonary hypertension
Cardiovascular Therapeutics, 2012Co-Authors: David B Badesch, Adaani E Frost, Michael D Mcgoon, Ronald J Oudiz, Shelley Shapiro, Jeremy Feldman, A Keogh, Michael A Mathier, Harrison W Farber, Martine AllardAbstract:SUMMARY 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 evalu- ating efficacy and safety of Ambrisentan in patients with various PH etiologies and back- ground 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%), con- nective tissue disease (18%), chronic hypoxemia (22%), chronic thromboembolic disease (13%), or other etiologies (16%) were enrolled and 53% of patients received stable back- ground 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 ob- served 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 deter- mined and larger, controlled studies will be necessary to determine the efficacy and safety of Ambrisentan in these populations.
Nazzareno Galie - One of the best experts on this subject based on the ideXlab platform.
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initial combination therapy with Ambrisentan tadalafil on pulmonary arterial hypertension related hospitalization in the ambition trial
Journal of Heart and Lung Transplantation, 2019Co-Authors: Jeanluc Vachiery, Adaani E Frost, Vallerie V Mclaughlin, Nazzareno Galie, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Marius M Hoeper, Andrew J Peacock, Gerald SimonneauAbstract:BACKGROUND In the randomized, double-blind, event-driven AMBITION study, initial combination therapy with Ambrisentan and tadalafil was associated with a 50% reduction in risk of clinical failure (first occurrence of all-cause death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) vs pooled monotherapy. These results were primarily driven by a reduction in PAH-related hospitalization in the combination therapy group, although a significant effect was not observed in a post-hoc analysis of all-cause hospitalization. METHODS The effect of initial combination therapy with Ambrisentan and tadalafil in AMBITION was further explored to study PAH-related hospitalization, which was not reported in the primary publication. RESULTS Initial combination therapy was associated with a 63% reduction in risk of PAH-related hospitalization when compared with pooled monotherapy (hazard ratio [HR] 0.372, 95% confidence interval [CI] 0.217 to 0.639, p = 0.0002). For every 9 patients treated with combination therapy vs monotherapy, 1 PAH-related hospitalization could be prevented over a 1-year period. Serious adverse events leading to hospitalization, not necessarily PAH-related, occurred in 87 of 253 (34%) and 89 of 247 (36%) of patients on combination therapy and pooled monotherapy, respectively (post-hoc summary). CONCLUSIONS Initial combination therapy with Ambrisentan and tadalafil was found to reduce the risk of PAH-related hospitalization by 63% compared with pooled monotherapy.
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initial use of Ambrisentan plus tadalafil in pulmonary arterial hypertension
The New England Journal of Medicine, 2015Co-Authors: Nazzareno Galie, Adaani E Frost, Vallerie V Mclaughlin, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Marius M Hoeper, Andrew J Peacock, Gerald Simonneau, Jeanluc Vachiery, Ekkehard GrünigAbstract:The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the Ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooledmonotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro–brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, −67.2% vs. −50.4%; P<0.001), as well as a higher percentage of pa tients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P = 0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia. CONCLUSIONS Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with Ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with Ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.)
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initial combination therapy with Ambrisentan and tadalafil in connective tissue disease associated pulmonary arterial hypertension ctd pah subgroup analysis from the ambition trial
Annals of the Rheumatic Diseases, 2015Co-Authors: J G Coghlan, Adaani E Frost, Vallerie V Mclaughlin, Nazzareno Galie, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Marius M Hoeper, Andrew J Peacock, Masataka Kuwana, Gerald SimonneauAbstract:Background Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. Objective To explore the safety and efficacy of initial combination therapy with Ambrisentan and tadalafil versus Ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. Methods This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with Ambrisentan plus tadalafil or monotherapy with Ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). Results In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. Conclusions This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial Ambrisentan and tadalafil combination therapy. Trial registration number NCT01178073, post results.
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long term Ambrisentan therapy for the treatment of pulmonary arterial hypertension
Journal of the American College of Cardiology, 2009Co-Authors: Ronald J Oudiz, Adaani E Frost, Horst Olschewski, Vallerie V Mclaughlin, David B Badesch, Michael D Mcgoon, Nazzareno Galie, Fernando Torres, Hossein Ardeschir Ghofrani, Ellen B RoeckerAbstract: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 >3× the upper limit of normal was ∼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 )
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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, 2008Co-Authors: Nazzareno Galie, Adaani E Frost, Horst Olschewski, Vallerie V Mclaughlin, David B Badesch, Michael D Mcgoon, Ronald J Oudiz, Fernando Torres, Hossein Ardeschir Ghofrani, Ellen B RoeckerAbstract: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 trea...
Ronald J Oudiz - One of the best experts on this subject based on the ideXlab platform.
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clinical and hemodynamic improvements after adding Ambrisentan to background pde5i therapy in patients with pulmonary arterial hypertension exhibiting a suboptimal therapeutic response athena 1
Respiratory Medicine, 2017Co-Authors: Shelley Shapiro, Hunter Gillies, Martine Allard, Fernando Torres, Christiana Blair, Jeremy Feldman, A Keogh, James Tislow, Ronald J OudizAbstract:Abstract Objective Pulmonary arterial hypertension (PAH) is a condition which may lead to right ventricular failure and premature death. While recent data supports the initial combination of Ambrisentan (a selective ERA) and tadalafil (a PDE5i) in functional class II or III patients, there is no published data describing the safety and efficacy of Ambrisentan when added to patients currently receiving a PDE5i and exhibiting a suboptimal response. The ATHENA-1 study describes the safety and efficacy of the addition of Ambrisentan in this patient population. Methods PAH patients with a suboptimal response to current PDE5i monotherapy were assigned Ambrisentan in an open-label fashion and evaluated for up to 48 weeks. Cardiopulmonary hemodynamics (change in PVR as primary endpoint) were evaluated at week 24 and functional parameters and biomarkers were measured through week 48. Time to clinical worsening (TTCW) and survival are also described. Results Thirty-three subjects were included in the analysis. At week 24, statistically significant improvements in PVR (−32%), mPAP (−11%), and CI (+25%) were observed. Hemodynamic improvements at week 24 were further supported by improvements in the secondary endpoints: 6-min walk distance (+18 m), NT-proBNP (−31%), and maintenance or improvement in WHO FC in 97% of patients. Adverse events were consistent with known effects of Ambrisentan. Conclusion The hemodynamic, functional, and biomarker improvements observed in the ATHENA-1 study suggests that the sequential addition of Ambrisentan to patients not having a satisfactory response to established PDE5i monotherapy is a reasonable option.
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initial combination therapy with Ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension a secondary analysis of the results from the randomised controlled ambition study
The Lancet Respiratory Medicine, 2016Co-Authors: Marius M Hoeper, Adaani E Frost, Vallerie V Mclaughlin, Stephan Rosenkranz, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Andrew J Peacock, Gerald Simonneau, Ronald J OudizAbstract:Summary Background In treatment-naive patients with pulmonary arterial hypertension, initial combination therapy with Ambrisentan and tadalafil reduces the risk of clinical failure events compared with monotherapy. We did this secondary analysis to further investigate the effect of combination therapy on survival. Methods We analysed survival data from the modified intention-to-treat population of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial. AMBITION was a multicentre, randomised, double-blind study, in which treatment-naive patients with pulmonary arterial hypertension were randomly assigned in a 2:1:1 ratio and received combination therapy with Ambrisentan and tadalafil, Ambrisentan and placebo, or tadalafil and placebo. We did a prespecified analysis of all mortality events from randomisation to the end of the study, including patients who discontinued their assigned treatment. In a post-hoc analysis, we analysed survival at 7 days after the termination of each individual patient's randomised treatment. We used Cox proportional hazard regression, Kaplan-Meier survival estimates, and the stratified log-rank test to compare the survival of patients receiving initial combination therapy or initial monotherapy. Findings The study population consisted of 605 patients with pulmonary arterial hypertension who were randomly assigned and received combination therapy (n=302) or monotherapy (n=303; 152 patients assigned to Ambrisentan monotherapy and 151 patients to tadalafil monotherapy). At the end of the study, 29 (10%) of 302 patients in the combination therapy group had died compared with 41 (14%) of 303 patients in the monotherapy group (hazard ratio 0·67, 95% CI 0·42–1·08; stratified log-rank p=0·10). At 7 days after the end of randomised treatment, fewer patients had died in the combination therapy group (3 [1%] of 302 patients) compared with the monotherapy group (13 [4%] of 303 patients; hazard ratio 0·21, 95% CI 0·06–0·73). Interpretation These data indicate that initial combination therapy might be associated with a survival advantage compared with initial monotherapy in patients with newly diagnosed pulmonary arterial hypertension. This hypothesis needs to be addressed in future studies. Funding Gilead, GlaxoSmithKline.
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aries 3 Ambrisentan therapy in a diverse population of patients with pulmonary hypertension
Cardiovascular Therapeutics, 2012Co-Authors: David B Badesch, Adaani E Frost, Michael D Mcgoon, Ronald J Oudiz, Shelley Shapiro, Jeremy Feldman, A Keogh, Michael A Mathier, Harrison W Farber, Martine AllardAbstract:SUMMARY 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 evalu- ating efficacy and safety of Ambrisentan in patients with various PH etiologies and back- ground 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%), con- nective tissue disease (18%), chronic hypoxemia (22%), chronic thromboembolic disease (13%), or other etiologies (16%) were enrolled and 53% of patients received stable back- ground 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 ob- served 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 deter- mined and larger, controlled studies will be necessary to determine the efficacy and safety of Ambrisentan in these populations.
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long term pulmonary hemodynamic effects of Ambrisentan in pulmonary arterial hypertension
American Journal of Cardiology, 2011Co-Authors: James R Klinger, Darrin Despain, Rebecca Spence, Ronald J Oudiz, Christopher DuftonAbstract: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
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long term Ambrisentan therapy for the treatment of pulmonary arterial hypertension
Journal of the American College of Cardiology, 2009Co-Authors: Ronald J Oudiz, Adaani E Frost, Horst Olschewski, Vallerie V Mclaughlin, David B Badesch, Michael D Mcgoon, Nazzareno Galie, Fernando Torres, Hossein Ardeschir Ghofrani, Ellen B RoeckerAbstract: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 >3× the upper limit of normal was ∼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 )
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initial combination therapy with Ambrisentan tadalafil on pulmonary arterial hypertension related hospitalization in the ambition trial
Journal of Heart and Lung Transplantation, 2019Co-Authors: Jeanluc Vachiery, Adaani E Frost, Vallerie V Mclaughlin, Nazzareno Galie, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Marius M Hoeper, Andrew J Peacock, Gerald SimonneauAbstract:BACKGROUND In the randomized, double-blind, event-driven AMBITION study, initial combination therapy with Ambrisentan and tadalafil was associated with a 50% reduction in risk of clinical failure (first occurrence of all-cause death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) vs pooled monotherapy. These results were primarily driven by a reduction in PAH-related hospitalization in the combination therapy group, although a significant effect was not observed in a post-hoc analysis of all-cause hospitalization. METHODS The effect of initial combination therapy with Ambrisentan and tadalafil in AMBITION was further explored to study PAH-related hospitalization, which was not reported in the primary publication. RESULTS Initial combination therapy was associated with a 63% reduction in risk of PAH-related hospitalization when compared with pooled monotherapy (hazard ratio [HR] 0.372, 95% confidence interval [CI] 0.217 to 0.639, p = 0.0002). For every 9 patients treated with combination therapy vs monotherapy, 1 PAH-related hospitalization could be prevented over a 1-year period. Serious adverse events leading to hospitalization, not necessarily PAH-related, occurred in 87 of 253 (34%) and 89 of 247 (36%) of patients on combination therapy and pooled monotherapy, respectively (post-hoc summary). CONCLUSIONS Initial combination therapy with Ambrisentan and tadalafil was found to reduce the risk of PAH-related hospitalization by 63% compared with pooled monotherapy.
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initial combination therapy with Ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension a secondary analysis of the results from the randomised controlled ambition study
The Lancet Respiratory Medicine, 2016Co-Authors: Marius M Hoeper, Adaani E Frost, Vallerie V Mclaughlin, Stephan Rosenkranz, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Andrew J Peacock, Gerald Simonneau, Ronald J OudizAbstract:Summary Background In treatment-naive patients with pulmonary arterial hypertension, initial combination therapy with Ambrisentan and tadalafil reduces the risk of clinical failure events compared with monotherapy. We did this secondary analysis to further investigate the effect of combination therapy on survival. Methods We analysed survival data from the modified intention-to-treat population of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial. AMBITION was a multicentre, randomised, double-blind study, in which treatment-naive patients with pulmonary arterial hypertension were randomly assigned in a 2:1:1 ratio and received combination therapy with Ambrisentan and tadalafil, Ambrisentan and placebo, or tadalafil and placebo. We did a prespecified analysis of all mortality events from randomisation to the end of the study, including patients who discontinued their assigned treatment. In a post-hoc analysis, we analysed survival at 7 days after the termination of each individual patient's randomised treatment. We used Cox proportional hazard regression, Kaplan-Meier survival estimates, and the stratified log-rank test to compare the survival of patients receiving initial combination therapy or initial monotherapy. Findings The study population consisted of 605 patients with pulmonary arterial hypertension who were randomly assigned and received combination therapy (n=302) or monotherapy (n=303; 152 patients assigned to Ambrisentan monotherapy and 151 patients to tadalafil monotherapy). At the end of the study, 29 (10%) of 302 patients in the combination therapy group had died compared with 41 (14%) of 303 patients in the monotherapy group (hazard ratio 0·67, 95% CI 0·42–1·08; stratified log-rank p=0·10). At 7 days after the end of randomised treatment, fewer patients had died in the combination therapy group (3 [1%] of 302 patients) compared with the monotherapy group (13 [4%] of 303 patients; hazard ratio 0·21, 95% CI 0·06–0·73). Interpretation These data indicate that initial combination therapy might be associated with a survival advantage compared with initial monotherapy in patients with newly diagnosed pulmonary arterial hypertension. This hypothesis needs to be addressed in future studies. Funding Gilead, GlaxoSmithKline.
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initial use of Ambrisentan plus tadalafil in pulmonary arterial hypertension
The New England Journal of Medicine, 2015Co-Authors: Nazzareno Galie, Adaani E Frost, Vallerie V Mclaughlin, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Marius M Hoeper, Andrew J Peacock, Gerald Simonneau, Jeanluc Vachiery, Ekkehard GrünigAbstract:The primary analysis included 500 participants; 253 were assigned to the combination-therapy group, 126 to the Ambrisentan-monotherapy group, and 121 to the tadalafil-monotherapy group. A primary end-point event occurred in 18%, 34%, and 28% of the participants in these groups, respectively, and in 31% of the pooledmonotherapy group (the two monotherapy groups combined). The hazard ratio for the primary end point in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35 to 0.72; P<0.001). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro–brain natriuretic peptide levels than did the pooled-monotherapy group (mean change, −67.2% vs. −50.4%; P<0.001), as well as a higher percentage of pa tients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56 [95% CI, 1.05 to 2.32]; P = 0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; P<0.001). The adverse events that occurred more frequently in the combination-therapy group than in either monotherapy group included peripheral edema, headache, nasal congestion, and anemia. CONCLUSIONS Among participants with pulmonary arterial hypertension who had not received previous treatment, initial combination therapy with Ambrisentan and tadalafil resulted in a significantly lower risk of clinical-failure events than the risk with Ambrisentan or tadalafil monotherapy. (Funded by Gilead Sciences and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.)
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initial combination therapy with Ambrisentan and tadalafil in connective tissue disease associated pulmonary arterial hypertension ctd pah subgroup analysis from the ambition trial
Annals of the Rheumatic Diseases, 2015Co-Authors: J G Coghlan, Adaani E Frost, Vallerie V Mclaughlin, Nazzareno Galie, Joan Albert Barbera, Hossein Ardeschir Ghofrani, Marius M Hoeper, Andrew J Peacock, Masataka Kuwana, Gerald SimonneauAbstract:Background Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH. Objective To explore the safety and efficacy of initial combination therapy with Ambrisentan and tadalafil versus Ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial. Methods This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with Ambrisentan plus tadalafil or monotherapy with Ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response). Results In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups. Conclusions This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial Ambrisentan and tadalafil combination therapy. Trial registration number NCT01178073, post results.
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long term Ambrisentan therapy for the treatment of pulmonary arterial hypertension
Journal of the American College of Cardiology, 2009Co-Authors: Ronald J Oudiz, Adaani E Frost, Horst Olschewski, Vallerie V Mclaughlin, David B Badesch, Michael D Mcgoon, Nazzareno Galie, Fernando Torres, Hossein Ardeschir Ghofrani, Ellen B RoeckerAbstract: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 >3× the upper limit of normal was ∼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 )