title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  Gilead, GlaxoSmithKline.
authors.affiliation: Department of Respiratory Medicine, Hannover Medical School and German Centre for Lung Research, Hannover, Germany. Electronic address: hoeper.marius@mh-hannover.de.
authors.forename: Marius M
authors.initials: MM
authors.lastname: Hoeper
authors.affiliation: Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Vallerie V
authors.initials: VV
authors.lastname: McLaughlin
authors.affiliation: Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer and University of Barcelona, Barcelona, Spain; Biomedical Research Networking Center on Respiratory Diseases, Madrid, Spain.
authors.forename: Joan Albert
authors.initials: JA
authors.lastname: Barberá
authors.affiliation: Institute of Academic Medicine and the Houston Methodist Lung Center, Houston, TX, USA.
authors.forename: Adaani E
authors.initials: AE
authors.lastname: Frost
authors.affiliation: Universities of Giessen and Marburg Lung Center, Giessen, Germany.
authors.forename: Hossein-Ardeschir
authors.initials: HA
authors.lastname: Ghofrani
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, Paris, France; AP-HP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire Thorax Innovation, Service de Pneumologie, Hôpital de Bicêtre, Paris, France; UMR S 999, INSERM, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Paris, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.affiliation: Department of Cardiology and Cologne Cardiovascular Research Centre, University of Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Rosenkranz
authors.affiliation: Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Oudiz
authors.affiliation: University of Rochester, Rochester, NY, USA.
authors.forename: R James
authors.initials: RJ
authors.lastname: White
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Miller
authors.affiliation: GlaxoSmithKline, Uxbridge, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Langley
authors.affiliation: GlaxoSmithKline, Uxbridge, UK.
authors.forename: Julia H N
authors.initials: JHN
authors.lastname: Harris
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Christiana
authors.initials: C
authors.lastname: Blair
authors.affiliation: University of California at San Diego, La Jolla, CA, USA.
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Rubin
authors.affiliation: Universitaires de Bruxelles-Hôpital Erasme, Brussels, Belgium.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Vachiery
mesh_terms: D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000401:mortality*; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010666:Phenylpropionates / Q000008:administration & dosage*; D016016:Proportional Hazards Models; D011651:Pulmonary Artery; D011724:Pyridazines / Q000008:administration & dosage*; D000068581:Tadalafil / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D010666:Phenylpropionates; D011724:Pyridazines; D000068581:Tadalafil; C467894:ambrisentan