Survival after the initiation of combination therapy in patients with pulmonary arterial hypertension: an Australian collaborative report


  • Funding: This study was conducted independently under the supervision of the authors. No pharmaceutical companies were involved in the study design, data collection, data analysis or interpretation.

  • Conflict of interest: AK has participated in clinical trials with Actelion Pharmaceuticals Australia, Bayer, GSK, Heartware, Myogen, Novartis, Pfizer, Roche, Scios, Ventracor and Wyeth. She has served on Advisory Boards for Actelion Pharmaceuticals Australia, Bayer, CSL, GSK, Novartis, Pfizer, Roche and Ventracor. GS has received honorarium for speaking at Pfizer and Actelion sponsored events. EK has participated in clinical trials with Actelion, Bayer, GSK, Novartis and Pfizer. EK is on the Scientific Advisory Board for Actelion, Pfizer and GSK. He has received honorarium for speaking at Actelion, Pfizer and GSK sponsored events. DK is on the Scientific Advisory Board for Pfizer, Actelion and GSK. TJW is a PAH Scientific Advisory Board member for Actelion Pharmaceuticals Australia, CSL and GSK. He has received travel and research support/investigator payments from Actelion and research support/investigator payments from Bayer, CSL, Pfizer and United Therapeutics. PS has participated in clinical trials with Actelion and is on the Advisory Board for Actelion. EG has received research support from Actelion Pharmaceuticals Australia, CSL, as well as honoraria for speaking and consulting engagements, and as a member of the Actelion, CSL and GSK Advisory Boards. The Heart and Lung Transplant Foundation of WA, of which EG is chair, has received educational grants from Actelion and CSL. KB and AP have been on Advisory Boards for Pfizer. BD has received consultancy fees from Actelion. EG has also received travel support from Bayer-Schering, the manufacturers of Iloprost, Encysive Pharmaceuticals, the manufacturers of Sitaxentan and GSK, the distributors of Ambrisentan in Australia.

Anne Keogh, St Vincent's Hospital, Xavier 4, Victoria St, Darlinghurst, NSW 2010, Australia.


Background:  Several cellular pathways are implicated in the pathogenesis of pulmonary arterial hypertension (PAH) and attempts to arrest disease progression with a single drug would not be expected to succeed in the medium term. In clinical practice, combination therapy is often used in patients deteriorating on monotherapy, despite the absence of firm evidence from randomized controlled controls.

Methods:  From January 2005 to August 2009, 112 patients with World Health Organisation Functional Class (FC) II–IV PAH deteriorating on monotherapy received non-parenteral combination therapy at six Australian PAH expert hospitals. Combination therapy included bosentan, sitaxentan, ambrisentan, iloprost and sildenafil. Data were prospectively collected for survival status, 6-min walk distance, FC and echocardiographic parameters at the start of monotherapy through to commencement of combination therapy and at 6-monthly intervals thereafter.

Results:  After varying periods of monotherapy (18.7 ± 13.4 months), survival estimates on combination therapy were 88%, 71% and 61% for the additional 1, 2 and 3 years respectively. Survival on dual therapy in patients with idiopathic PAH/familial PAH was 93% at 1 year and 79% at 2 years, and for scleroderma-related PAH, 72% at 1 year and 48% at year 2 after initiation of combination therapy. In survivors, dual therapy reversed the deterioration in FC, from 3.1 ± 0.6 on monotherapy to 2.2 ± 0.6 at 12 months. Similarly, dual therapy improved 6-min walk distance from 316 ± 119 m to 406 ± 129 m at 12 months, and sequential echocardiography demonstrated a fall in pulmonary artery systolic pressure and improved right ventricular function.

Conclusions:  Dual non-parenteral therapy appears safe and effective and should be considered for PAH patients who are deteriorating on monotherapy to improve long-term outcomes.