Clinical outcomes stratified by baseline functional class after initial combination therapy for pulmonary arterial hypertension

R James White,Hossein-Ardeschir Ghofrani,Joan A Barberà,Jonathan Langley,Adaani E Frost,Vallerie V Mclaughlin,Marius M Hoeper,Murali M Chakinala,Ekkehard Grünig,Ronald J Oudiz,Stephan Rosenkranz,Christiana Blair,Anton Vonk-Noordegraaf

doi:10.1186/s12931-019-1180-1

Abstract

BackgroundInitial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure events for treatment-naïve participants with pulmonary arterial hypertension (PAH) as compared to monotherapy. Previous studies in PAH have demonstrated greater treatment benefits in more symptomatic participants.MethodsAMBITION was an event-driven, double-blind study in which participants were randomized 2:1:1 to once-daily initial combination therapy with ambrisentan 10 mg plus tadalafil 40 mg, ambrisentan 10 mg plus placebo, or tadalafil 40 mg plus placebo. In this pre-specified subgroup analysis, we compared the efficacy data between those with functional class (FC) II vs. FC III symptoms at baseline.ResultsThis analysis included 500 participants in the previously defined primary analysis set (n = 155 FC II, n = 345 FC III). Comparing combination therapy to pooled monotherapy, the risk of clinical failure events was reduced by 79% (hazard ratio, 0.21 [95% confidence interval: 0.071, 0.63]) for FC II patients and 42% (hazard ratio, 0.58 [95% confidence interval: 0.39, 0.86]) for FC III patients. In a post-hoc analysis, the risk of first hospitalization for worsening PAH was also reduced by combination therapy, particularly for FC II patients (0 combination vs. 11 [14%] pooled monotherapy). Adverse events were frequent but comparable between the subgroups.ConclusionsTreatment benefit from initial combination therapy appeared at least as great for FC II as for FC III participants. Hospitalizations for worsening PAH were not observed in FC II participants assigned to combination. The present data support an initial combination strategy for newly diagnosed patients even when symptoms are less severe.Funded by Gilead Sciences, Inc. and GlaxoSmithKline; AMBITION ClinicalTrials.gov number, NCT01178073.

Highlights

Initial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure events for treatment-naïve participants with pulmonary arterial hypertension (PAH) as compared to monotherapy
The present paper describes a prespecified subgroup analysis which planned to evaluate the primary outcome in participants with functional class (FC) II symptoms as compared to those with more advanced FC III symptoms
More males with FC II symptoms were randomized to combination therapy; otherwise treatment assignments were balanced

Summary

Introduction

Initial combination therapy with ambrisentan and tadalafil reduced the risk of clinical failure events for treatment-naïve participants with pulmonary arterial hypertension (PAH) as compared to monotherapy. Previous studies in PAH have demonstrated greater treatment benefits in more symptomatic participants. Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature characterized by vasoconstriction, vascular inflammation and fibrosis, and in situ thrombosis [1]. The AMBITION study demonstrated a 50% reduction in the risk of clinical failure for treatment naïve PAH participants who began initial combination therapy (ambrisentan and tadalafil) as compared to those assigned. The benefit of initial combination therapy was primarily attributable to a reduction in PAH-related hospitalizations. We hypothesized that the statistically and clinically relevant benefits of initial combination therapy would be largely attributable to those with FC III symptoms at baseline

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