Upfront combination therapy: does the AMBITION study herald a new era in the treatment of pulmonary arterial hypertension?

A new treatment paradigm for pulmonary arterial hypertension (PAH) has emerged, heralded by the recently published results of the AMBITION study in a recent issue of the New England Journal of Medicine .1 While the practice of combination therapy is not new, this has previously been implemented in a sequential fashion. The AMBITION study is the first study comparing the use of upfront combination therapy in patients with treatment-naive incident PAH who were randomised to therapy with ambrisentan plus tadalafil versus ambrisentan or tadalafil monotherapy. The results were initially presented at the European Respiratory Society meeting in September 2014 with the primary publication in the New England Journal of Medicine in August 2015.1 The primary efficacy endpoint of the AMBITION study was time to first clinical failure (TTCF) defined as either death, hospitalisation for worsening PAH, disease progression (>15% decline in 6 min walk test (MWT) from baseline with WHO functional class III or IV symptoms) or unsatisfactory clinical response (WHO functional class III symptoms while in the study for at least 6 months with a decrease in 6 MWT distance from baseline). The latter three events were all adjudicated and multiple secondary endpoints, including change in the 6 min walk distance, were also evaluated. There were 610 patients enrolled in the study of whom 500 constituted the primary analysis set (PAS).1 The other 105 patients were excluded from the PAS after a protocol amendment aimed at excluding those patients with risk factors for left ventricular diastolic dysfunction. Patients were randomised in a 2:1:1 fashion to upfront combination therapy or monotherapy with ambrisentan or tadalafil. The study demonstrated unequivocally that upfront combination therapy was indeed superior to monotherapy with either single agent based on the selected end points of the study. The HR for TTCF for combination therapy compared with the …