title: Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension.
abstract: BACKGROUND
  Data on the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension are scarce.
  
  
  METHODS
  In this event-driven, double-blind study, we randomly assigned, in a 2:1:1 ratio, participants with World Health Organization functional class II or III symptoms of pulmonary arterial hypertension who had not previously received treatment to receive initial combination therapy with 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentan-monotherapy group), or 40 mg of tadalafil plus placebo (tadalafil-monotherapy group), all administered once daily. The primary end point in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening pulmonary arterial hypertension, disease progression, or unsatisfactory long-term clinical response.
  
  
  RESULTS
  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 pooled-monotherapy 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 patients 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.).
authors: From the Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy (N.G.); Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer and University of Barcelona, Barcelona, and Biomedical Research Networking Center on Respiratory Diseases, Madrid (J.A.B.); Baylor College of Medicine, Houston (A.E.F.); Universities of Giessen and Marburg Lung Center, Giessen (H.-A.G.), Hanover Medical School and German Center of Lung Research, Hanover (M.M.H.), and Thoraxklinik at University Hospital Heidelberg, Heidelberg (E.G.) - all in Germany; University of Michigan Health System, Ann Arbor (V.V.M.); Regional Heart and Lung Centre, Glasgow (A.J.P.), and GlaxoSmithKline, Uxbridge (J.H.N.H., J.L.) - both in the United Kingdom; Université Paris-Sud, Faculté de Médecine, and Assistance Publique-Hôpitaux de Paris, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire Thorax Innovation, Service de Pneumologie, Hôpital de Bicêtre, Le Kremlin Bicêtre, INSERM Unité Mixté de Recherche S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson - all in France (G.S.); Universitaires de Bruxelles-Hôpital Erasme, Brussels (J.-L.V.); Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance (R.J.O.), Gilead Sciences, Foster City (C.B., H.G., K.L.M.), and University of California at San Diego, La Jolla (L.J.R.) - all in California; VU University Medical Center, Amsterdam (A.V.-N.); and the University of Rochester, Rochester, NY (R.J.W.).
authors: Nazzareno
authors: N
authors: Galiè
authors: Joan A
authors: JA
authors: Barberà
authors: Adaani E
authors: AE
authors: Frost
authors: Hossein-Ardeschir
authors: HA
authors: Ghofrani
authors: Marius M
authors: MM
authors: Hoeper
authors: Vallerie V
authors: VV
authors: McLaughlin
authors: Andrew J
authors: AJ
authors: Peacock
authors: Gérald
authors: G
authors: Simonneau
authors: Jean-Luc
authors: JL
authors: Vachiery
authors: Ekkehard
authors: E
authors: Grünig
authors: Ronald J
authors: RJ
authors: Oudiz
authors: Anton
authors: A
authors: Vonk-Noordegraaf
authors: R James
authors: RJ
authors: White
authors: Christiana
authors: C
authors: Blair
authors: Hunter
authors: H
authors: Gillies
authors: Karen L
authors: KL
authors: Miller
authors: Julia H N
authors: JH
authors: Harris
authors: Jonathan
authors: J
authors: Langley
authors: Lewis J
authors: LJ
authors: Rubin
mesh_terms: D000328:Adult; D000368:Aged; D002243:Carbolines / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006760:Hospitalization; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D010666:Phenylpropionates / Q000009:adverse effects / Q000627:therapeutic use*; D011724:Pyridazines / Q000009:adverse effects / Q000627:therapeutic use*; D012307:Risk Factors; D000068581:Tadalafil
chemical_list: D002243:Carbolines; D010446:Peptide Fragments; D010666:Phenylpropionates; D011724:Pyridazines; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D000068581:Tadalafil; C467894:ambrisentan