Marius M Hoeper1, Vallerie V McLaughlin2, Joan Albert Barberá3, Adaani E Frost4, Hossein-Ardeschir Ghofrani5, Andrew J Peacock6, Gérald Simonneau7, Stephan Rosenkranz8, Ronald J Oudiz9, R James White10, Karen L Miller11, Jonathan Langley12, Julia H N Harris12, Christiana Blair11, Lewis J Rubin13, Jean-Luc Vachiery14. 1. Department of Respiratory Medicine, Hannover Medical School and German Centre for Lung Research, Hannover, Germany. Electronic address: hoeper.marius@mh-hannover.de. 2. Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA. 3. 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. 4. Institute of Academic Medicine and the Houston Methodist Lung Center, Houston, TX, USA. 5. Universities of Giessen and Marburg Lung Center, Giessen, Germany. 6. Regional Heart and Lung Centre, Glasgow, UK. 7. 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. 8. Department of Cardiology and Cologne Cardiovascular Research Centre, University of Cologne, Germany. 9. Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA. 10. University of Rochester, Rochester, NY, USA. 11. Gilead Sciences, Foster City, CA, USA. 12. GlaxoSmithKline, Uxbridge, UK. 13. University of California at San Diego, La Jolla, CA, USA. 14. Universitaires de Bruxelles-Hôpital Erasme, Brussels, Belgium.
Abstract
BACKGROUND: 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. METHODS: 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. FINDINGS: 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 toambrisentan 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). INTERPRETATION: 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. FUNDING: Gilead, GlaxoSmithKline.
RCT Entities:
BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Gilead, GlaxoSmithKline.
Authors: Gustavo A Heresi; Thomas E Love; Adriano R Tonelli; Kristin B Highland; Raed A Dweik Journal: Am J Respir Crit Care Med Date: 2018-10-15 Impact factor: 21.405
Authors: Charles D Burger; Mohamedanwar Ghandour; Divya Padmanabhan Menon; Haytham Helmi; Raymond L Benza Journal: Clinicoecon Outcomes Res Date: 2017-11-24
Authors: Masataka Kuwana; Christiana Blair; Tomohiko Takahashi; Jonathan Langley; John G Coghlan Journal: Ann Rheum Dis Date: 2020-03-11 Impact factor: 19.103