Clinical and hemodynamic improvements after adding ambrisentan to background PDE5i therapy in patients with pulmonary arterial hypertension exhibiting a suboptimal therapeutic response (ATHENA-1)

• Published in: Respiratory medicine Vol. 126; pp. 84 - 92
• Main Authors: Shapiro, Shelley, Torres, Fernando, Feldman, Jeremy, Keogh, Anne, Allard, Martine, Blair, Christiana, Gillies, Hunter, Tislow, James, Oudiz, Ronald J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2017; Elsevier Limited
• Subjects: Adult; Age; Ambrisentan; Antihypertensive Agents - therapeutic use; Arteries; Biomarkers - metabolism; Blood pressure; Brain natriuretic peptide; Chest; Clinical outcomes; Clinical trials; Combination drug therapy; Contraction; Coronary artery disease; Death; Dose-Response Relationship, Drug; Drug therapy; Drug Therapy, Combination - methods; Dyspnea; Elapid Venoms; Endothelin A receptor antagonist; Endothelin A Receptor Antagonists - therapeutic use; Ethics; Exercise Tolerance - drug effects; Female; Heart diseases; Hemodynamics; Hemodynamics - drug effects; Humans; Hypertension; Hypertension, Pulmonary - classification; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - physiopathology; Male; Middle Aged; Mortality; Natriuretic Peptide, C-Type - drug effects; Outcome assessment; Outcome Assessment (Health Care); pH effects; Pharmacokinetics; Phenylpropionates - administration & dosage; Phenylpropionates - adverse effects; Phenylpropionates - pharmacology; Phosphodiesterase 5 inhibitor; Phosphodiesterase 5 Inhibitors - therapeutic use; Physical fitness; Pulmonary arteries; Pulmonary Hypertension; Pulmonary/Respiratory; Pyridazines - administration & dosage; Pyridazines - adverse effects; Pyridazines - pharmacology; Respiration; Statistical analysis; Survival; Tadalafil - administration & dosage; Tadalafil - pharmacology; Treatment Outcome; Ventricle; Phosphodiesterase 5 inhibitor; Pulmonary Hypertension; Endothelin A receptor antagonist; Outcome assessment; Combination drug therapy; Ambrisentan
• ISSN: 0954-6111; 1532-3064; 1532-3064
• DOI: 10.1016/j.rmed.2017.03.025

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. 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. 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. 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. •This study evaluates the addition of ambrisentan to patients with an unsatisfactory response to PDE5i monotherapy.•The addition of ambrisentan was associated with hemodynamic, functional, and biomarker improvement compared to baseline.•Significant improvements were observed in PVR (−33%), mPAP (−11%), and CI (+24%) following 24 weeks of add-on ambrisentan.•At week 24, 6MWD, NT-proBNP, and WHO functional class showed improvements from baseline.•Adverse events were consistent with known effects of ambrisentan, but 10% of patients discontinued because of them.