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Ann Rheum Dis. 2017 Jul;76(7):1219-1227. doi: 10.1136/annrheumdis-2016-210236. Epub 2016 Dec 30.

Initial combination therapy with ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH): subgroup analysis from the AMBITION trial.

Author information

1
Cardiology Department, Royal Free Hospital, London, UK.
2
Department of Experimental, Diagnostic and Specialty Medicine-DIMES, University of Bologna, Bologna, Italy.
3
Department of Respiratory Medicine, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
4
Biomedical Research Networking Center on Respiratory Diseases, Madrid, Spain.
5
Houston Methodist Lung Center, Houston, Texas, USA.
6
Universities of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany.
7
Hannover Medical School and German Center of Lung Research (DZL) Hannover, Hannover, Germany.
8
Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine, Tokyo, Japan.
9
Univeristy of Michigan Health System, Ann Arbor, Michigan, USA.
10
Regional Heart and Lung Centre, Glasgow, UK.
11
Faculté de Médecine, Université Paris-Sud, Le Kremlin Bicêtre, France.
12
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.
13
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.
14
Universitaires de Bruxelles-Hôpital Erasme, Brussels, Belgium.
15
Gilead Sciences, Inc., Foster City, California, USA.
16
Former employee of Gilead Sciences, Inc., Foster City, California, USA.
17
GlaxoSmithKline, Uxbridge, UK.
18
University of California at San Diego, La Jolla, California, USA.

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.

TRIAL REGISTRATION NUMBER:

NCT01178073, post results.

KEYWORDS:

Arterial Hypertension; Systemic Sclerosis; Treatment

PMID:
28039187
PMCID:
PMC5530350
DOI:
10.1136/annrheumdis-2016-210236
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Competing interests: JGC: grants and personal fees from Actelion and GlaxoSmithKline; personal fees from Bayer, Endotronix, Pfizer and United Therapeutics. NG: grants and personal fees from Actelion, Bayer, GlaxoSmithKline and Pfizer. JAB: personal fees from Actelion, Almirall, Bayer, GlaxoSmithKline and Pfizer; grants from Actelion, Bayer, GlaxoSmithKline and Pfizer. AEF: funds for the conduct of the study from Baylor College of Medicine; honoraria and travel/lodging expense for participating on the study's Steering Committee; grants from Actelion, Bayer, Gilead and United Therapeutics; personal fees from Actelion, Bayer, Gilead, Ikaria and United Therapeutics; non-financial support from Bayer and Novartis. H-AG: grants from Actelion, Bayer, Novartis and Pfizer; board membership and consultancy for Actelion, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer and Takeda; consultancy for Lilly; payment for lectures from Actelion, Bayer, GlaxoSmithKline, Lilly, Novartis and Pfizer. MMH: personal fees from Actelion, Bayer, Gilead, GlaxoSmithKline, Merck and Pfizer. MK: grants and personal fees from Actelion, Bayer and Pfizer; personal fees from GlaxoSmithKline. VVM: grants and personal fees from Actelion, Bayer, Gilead, Ikaria and United Therapeutics; grants from Novartis; personal fees from Steadymed and Akros. AJP: grants and personal fees from Actelion, Bayer, Gilead and GlaxoSmithKline; personal fees from United Therapeutics. GS: grants and personal fees from Actelion, Bayer, Gilead and GlaxoSmithKline. J-LV: grants from Actelion and GlaxoSmithKline; speaker fees from Actelion, Bayer, GlaxoSmithKline and Pfizer; advisory board honoraria from Actelion and Merck. CB: employee of Gilead; stock options in Gilead. HG: former employee of Gilead; patent pending in relation to the use of selective ERA's and PDE5 inhibitors. KLM: employee of Gilead; stock options in Gilead. JHNH: employee of GlaxoSmithKline; stock options in GlaxoSmithKline. JL: employee of GlaxoSmithKline. LJR: personal fees from Gilead.

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