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

John Gerry Coghlan, Nazzareno Galiè, Joan Albert Barberà, Adaani E Frost, Hossein-Ardeschir Ghofrani, Marius M Hoeper, Masataka Kuwana, Vallerie V McLaughlin, Andrew J Peacock, Gérald Simonneau, Jean-Luc Vachiéry, Christiana Blair, Hunter Gillies, Karen L Miller, Julia H N Harris, Jonathan Langley, Lewis J Rubin, AMBITION investigators, John Gerry Coghlan, Nazzareno Galiè, Joan Albert Barberà, Adaani E Frost, Hossein-Ardeschir Ghofrani, Marius M Hoeper, Masataka Kuwana, Vallerie V McLaughlin, Andrew J Peacock, Gérald Simonneau, Jean-Luc Vachiéry, Christiana Blair, Hunter Gillies, Karen L Miller, Julia H N Harris, Jonathan Langley, Lewis J Rubin, AMBITION investigators

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.

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.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Figures

Figure 1
Figure 1
Flow chart of population distribution among the treatment arms. The modified intention-to-treat (mITT) population includes patients who were randomised and received study drug. The ex-primary analysis set (PAS) population includes patients who were randomised and received study drug but did not meet the amended entry criteria. The PAS population includes patients who were randomised, received study drug, and met the amended entry criteria. The last row of this figure is a post hoc summary. CTD, connective tissue disease; FAV, final assessment visit; PAH, pulmonary arterial hypertension; SSc, systemic sclerosis.
Figure 2
Figure 2
Kaplan-Meier curves for the time from randomisation to first adjudicated clinical failure in the (A) connective tissue disease-associated pulmonary arterial hypertension population and (B) systemic sclerosis-pulmonary arterial hypertension population. Post hoc figures. The HR is for combination versus pooled monotherapy.
Figure 3
Figure 3
Forest plot of time to first occurrence of clinical failure, clinical worsening, death, hospitalisation, disease progression and unsatisfactory long-term clinical response (ULTCR) in the (A) connective tissue disease-associated pulmonary arterial hypertension population and (B) systemic sclerosis-pulmonary arterial hypertension population. Post hoc figures. The HR is for combination versus pooled monotherapy.

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Source: PubMed

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