title: Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial.
abstract: 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.
  
  
  BACKGROUND
  NCT01178073, post results.
authors.affiliation: Cardiology Department, Royal Free Hospital, London, UK.
authors.forename: John Gerry
authors.initials: JG
authors.lastname: Coghlan
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy.
authors.forename: Nazzareno
authors.initials: N
authors.lastname: Galiè
authors.affiliation: Department of Respiratory Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.|Biomedical Research Networking Center on Respiratory Diseases, Madrid, Spain.
authors.forename: Joan Albert
authors.initials: JA
authors.lastname: Barberà
authors.affiliation: Houston Methodist Lung Center, Houston, Texas, USA.
authors.forename: Adaani E
authors.initials: AE
authors.lastname: Frost
authors.affiliation: Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany.
authors.forename: Hossein-Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
authors.affiliation: Hannover Medical School and German Center of Lung Research (DZL) Hannover, Hannover, Germany.
authors.forename: Marius M
authors.initials: MM
authors.lastname: Hoeper
authors.affiliation: Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kuwana
authors.affiliation: Univeristy of Michigan Health System, Ann Arbor, Michigan, USA.
authors.forename: Vallerie V
authors.initials: VV
authors.lastname: McLaughlin
authors.affiliation: Regional Heart and Lung Centre, Glasgow, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peacock
authors.affiliation: Faculté de Médecine, Université Paris-Sud, Le Kremlin Bicêtre, France.|Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Service de Pneumologie, AP-HP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Hôpital de Bicêtre, Le Kremlin Bicêtre, France.|Laboratoire d'Excellence (LabEx) en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), UMR_S 999, INSERM, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.affiliation: Universitaires de Bruxelles-Hôpital Erasme, Brussels, Belgium.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Vachiéry
authors.affiliation: Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Christiana
authors.initials: C
authors.lastname: Blair
authors.affiliation: Former employee of Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Hunter
authors.initials: H
authors.lastname: Gillies
authors.affiliation: Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Miller
authors.affiliation: GlaxoSmithKline, Uxbridge, UK.
authors.forename: Julia H N
authors.initials: JHN
authors.lastname: Harris
authors.affiliation: GlaxoSmithKline, Uxbridge, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Langley
authors.affiliation: University of California at San Diego, La Jolla, California, USA.
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Rubin
mesh_terms: D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D018450:Disease Progression; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004487:Edema / Q000139:chemically induced; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology; D008180:Lupus Erythematosus, Systemic / Q000150:complications; D008297:Male; D008875:Middle Aged; D008947:Mixed Connective Tissue Disease / Q000150:complications; D010666:Phenylpropionates / Q000627:therapeutic use*; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use*; D011724:Pyridazines / Q000627:therapeutic use*; D012595:Scleroderma, Systemic / Q000150:complications*; D000068581:Tadalafil / Q000627:therapeutic use*
chemical_list: D000959:Antihypertensive Agents; D010666:Phenylpropionates; D058986:Phosphodiesterase 5 Inhibitors; D011724:Pyridazines; D000068581:Tadalafil; C467894:ambrisentan
keywords: Arterial Hypertension; Systemic Sclerosis; Treatment