title: Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension.
abstract: BACKGROUND
  Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH.
  
  
  METHODS
  In this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints.
  
  
  RESULTS
  At 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05).
  
  
  CONCLUSIONS
  Up-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hassoun
authors.affiliation: 2 Division of Pulmonary & Critical Care Medicine, Stanford University School of Medicine, Stanford, California.
authors.forename: Roham T
authors.initials: RT
authors.lastname: Zamanian
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Damico
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Noah
authors.initials: N
authors.lastname: Lechtzin
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Rubina
authors.initials: R
authors.lastname: Khair
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Kolb
authors.affiliation: 3 Division of Cardiology, Department of Medicine, and.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Tedford
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Olivia L
authors.initials: OL
authors.lastname: Hulme
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Traci
authors.initials: T
authors.lastname: Housten
authors.affiliation: 3 Division of Cardiology, Department of Medicine, and.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pisanello
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Erica H
authors.initials: EH
authors.lastname: Pullins
authors.affiliation: 4 Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Celia P
authors.initials: CP
authors.lastname: Corona-Villalobos
authors.affiliation: 4 Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Stefan L
authors.initials: SL
authors.lastname: Zimmerman
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Gashouta
authors.affiliation: 5 Division of Pulmonary and Critical Care Medicine, The Cleveland Clinic, Cleveland, Ohio.
authors.forename: Omar A
authors.initials: OA
authors.lastname: Minai
authors.affiliation: 6 Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Fernando
authors.initials: F
authors.lastname: Torres
authors.affiliation: 7 Division of Pulmonary Medicine, Spectrum Health/Michigan State University, Grand Rapids, Michigan.
authors.forename: Reda E
authors.initials: RE
authors.lastname: Girgis
authors.affiliation: 6 Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and.
authors.forename: Kelly
authors.initials: K
authors.lastname: Chin
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Mathai
mesh_terms: D004359:Drug Therapy, Combination; D005260:Female; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000473:pathology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000188:drug therapy* / Q000209:etiology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood / Q000187:drug effects; D010666:Phenylpropionates / Q000097:blood / Q000627:therapeutic use*; D058986:Phosphodiesterase 5 Inhibitors / Q000097:blood / Q000627:therapeutic use; D011446:Prospective Studies; D011724:Pyridazines / Q000097:blood / Q000627:therapeutic use*; D012595:Scleroderma, Systemic / Q000097:blood / Q000150:complications*; D013318:Stroke Volume; D000068581:Tadalafil / Q000097:blood / Q000627:therapeutic use*; D014463:Ultrasonography; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D010666:Phenylpropionates; D058986:Phosphodiesterase 5 Inhibitors; D011724:Pyridazines; D020097:Natriuretic Peptide, Brain; D000068581:Tadalafil; C467894:ambrisentan
keywords: MRI; pulmonary arterial hypertension; therapy