Search

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., Competing Interests: 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/.)

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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)