Study Summary: AMBITION
Galiè N, Barberà JA, Frost AE, et al; AMBITION Investigators. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension.
N Engl J Med. 2015;373(9):834-844. doi: 10.1056/NEJMoa1413687.
Single class agent therapies target just 1 intracellular pathway implicated in pulmonary arterial hypertension (PAH) disease pathogenesis. Because no single pathway has a dominant pathogenic role, single class agents are often ineffective treatments for patients with PAH. Combination therapy may provide clinical benefits in patients who do not benefit from a single class agent, by targeting multiple mechanisms within the prostacyclin, nitric oxide, or endothelin disease pathway to increase the overall therapeutic effect. Although previous clinical trials investigated the addition of therapeutic agents to background-approved therapy in patients with PAH, the administration of a first-line combination therapy was not assessed.
Investigators of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial hypothesized that the administration of initial combination therapy with different class agents would improve long-term clinical outcomes in treatment-naïve patients. Investigators selected agents that targeted different intracellular pathways responsible for PAH and had no pharmacokinetic interactions to limit their combinatory therapeutic effects. Tadalafil (phosphodiesterase type 5 inhibitor) inhibits a messenger of the nitric oxide pathway and ambrisentan (antagonist of the endothelin-A receptor) facilitates the blockade of endothelin-mediated vasoconstriction.
Of the patients enrolled in the AMBITION trial (n = 500), more than 95% had never received treatment for PAH; the remainder had received treatment for less than 14 days. Most patients had a diagnosis of idiopathic PAH (53%) or PAH associated with connective tissue disease (37%). Patients enrolled had World Health Organization (WHO) functional class II or III symptoms of PAH clinical severity (measures of physical activity, dyspnea, fatigue, chest pain, and syncope); most of the population (69%) had WHO functional class III symptoms.
Patients were randomized 2:1:1, where the combination therapy group received ambrisentan and tadalafil (n = 253) and the monotherapy groups received placebo with either ambrisentan (n = 126) or tadalafil (n = 121). For the first weeks of the trial, enrolled patients received once-daily oral therapy with 20-mg tadalafil and 5-mg ambrisentan; increased doses of 40-mg tadalafil and 10-mg ambrisentan were administered for the remainder of study treatment. The trial measured safety and efficacy assessments of patients treated for a mean duration of 517 days across all study groups (from randomization to final assessment). The statistical significance of all primary and secondary clinical outcomes with combination therapy were compared with each monotherapy and with a pooled-monotherapy treatment group (combined clinical outcomes of both monotherapy groups). The combination therapy group had a significantly longer duration of treatment of 550 days compared with 484 days in the pooled-monotherapy group (P
As the primary end point of the AMBITION trial, safety and efficacy of combination therapy was evaluated by the first event of clinical failure up to the time of each patient’s final assessment (Table
). A total of 123 patients experienced a primary outcome of clinical failure, defined as death, worsening of PAH leading to hospitalization, disease progression, or unsatisfactory long-term clinical response. In an analysis of the composite primary end point, patients who received initial combination therapy with ambrisentan and tadalafil had a 50% lower risk of defined events of clinical failure than patients in the pooled-monotherapy group analysis (HR, 0.50; 95% CI, 0.35-0.72; P
<.001), at 52% and 47% with ambrisentan and tadalafil therapy, respectively. The group receiving combination therapy had significantly fewer first clinical failure events than patients receiving either monotherapy: 18% in the combination therapy group compared with 34% in the ambrisentan-monotherapy group (P
<.001) and 28% in the tadalafil-monotherapy group (P
The largest observed benefit of combination therapy compared with monotherapy was the primary end point of hospitalization for worsening PAH, lung or heart and lung transplantation, atrial septostomy, or initiation of parenteral prostanoid therapy. In the combination-therapy group, 4% of patients experienced hospitalization compared with 12% in the pooled-monotherapy group (14% with ambrisentan monotherapy and 10% with tadalafil monotherapy). The ambrisentan-monotherapy group had the highest incidence of disease progression (10%), and the tadalafil-monotherapy group had the lowest incidence (3%). PAH disease progression was defined in patients who had a more than 15% decrease in the 6-minute walk distance from baseline and WHO functional class III or IV symptoms at 2 consecutive visits (at least 14 days apart). Significantly fewer patients (P
<.001) treated with combination therapy (4%) than in the pooled-monotherapy group (6%) experienced disease progression.
In the patients who received study treatment for at least 6 months, an unsatisfactory long-term clinical response was defined in those with both WHO functional class III symptoms assessed at 2 clinic visits at least 6 months apart and a decrease from baseline in the 6-minute walk distance at 2 consecutive clinic visits at least 14 days apart. A higher proportion of patients treated with either monotherapy had an unsatisfactory response (9% in the ambrisentan group and 10% in the tadalafil group) compared with patients in the combination-therapy group (7%). Death from any cause was lowest with ambrisentan monotherapy (2%) and highest in the tadalafil group (5%); combination therapy led to death in 4% of patients.
In a secondary end point analysis, satisfactory clinical response was measured at week 24 in patients with an increase of 10% from baseline in the 6-minute walk distance, reduction or maintenance of WHO functional class I or II symptoms with improved exercise capacity, and an absence of clinical events. The rate of satisfactory clinical response was significantly (P
= .03) higher in the combination therapy group (39%) than in the pooled-monotherapy group (29%), but was not significantly higher (P
= .15) than in the group treated with ambrisentan monotherapy (31%). Although not statistically significant, of the 252 patients treated with combination therapy, 94 (37%) experienced improved symptoms of WHO criteria from baseline by week 24 compared with 81 (33%) of 244 patients treated with either ambrisentan or tadalafil monotherapy. In addition, fewer patients in the combination group experienced worsened symptoms across treatment groups.
In an analysis of the trial’s safety outcomes, discontinuation rates due to adverse events (AEs) were similar across treatment groups: 12% in the combination-therapy and tadalafil-monotherapy groups and 11% in the ambrisentan-monotherapy group. The most common AEs leading to discontinuation of the study treatment were dyspnea and peripheral edema. Rates of serious AEs were also similar across treatment groups: 41% in the tadalafil-monotherapy group and 36% with both ambrisentan monotherapy and combination therapy. The most common serious AEs were worsening of PAH and pneumonia, with the former occurring at a lower rate in the combination-therapy group (4%) compared with the ambrisentan-monotherapy group (9%) and the tadalafil-monotherapy group (7%).
Galiè N, Barberà JA, Frost AE, et al; AMBITION Investigators. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med
. 2015;373(9):834-844. doi: 10.1056/NEJMoa1413687.
Galiè N, Barberà JA, Frost AE, et al; AMBITION Investigators. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension [supplemental appendix]. N Engl J Med