Ambrisentan Plus Tadalafil in Pulmonary Arterial Hypertension

Study Questions:

What is the effect of initial combination therapy with ambrisentan and tadalafil on long-term outcomes in patients with pulmonary arterial hypertension (PAH)?


AMBITION was a double-blind study conducted to compare an initial strategy of 10 mg of ambrisentan plus 40 mg of tadalafil (combination-therapy group), 10 mg of ambrisentan plus placebo (ambrisentan monotherapy), or 40 mg of tadalafil plus placebo (tadalafil monotherapy), all administered once daily. Patients 18-75 years old with World Health Organization (WHO) functional class (FC) II or III symptoms of PAH were assigned in a 2:1:1 ratio. The primary endpoint in a time-to-event analysis was the first event of clinical failure, which was defined as the first occurrence of a composite of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term clinical response.


The primary analysis included 500 participants; 253 were assigned to the combination therapy, 126 to ambrisentan, and 121 to tadalafil. Mean age was 54 years, nearly 80% were female, about 35% had connective tissue disease (CTD), and 70% were WHO FC III. A primary endpoint event occurred in 18%, 34%, and 28% of the participants in the groups, respectively, and in 31% of the pooled monotherapy group. The hazard ratio for the primary endpoint in the combination-therapy group versus the pooled-monotherapy group was 0.50 (95% confidence interval [CI], 0.35-0.72; p < 0.001) with the strongest difference in hospitalization for worsening (4% for combination vs. 12% for combined monotherapy). At week 24, the combination-therapy group had greater reductions from baseline in N-terminal pro–B-type natriuretic peptide levels than did the pooled-monotherapy group (mean change, –67.2% vs. –50.4%; p < 0.001), as well as a higher percentage of patients with a satisfactory clinical response (39% vs. 29%; odds ratio, 1.56; 95% CI, 1.05-2.32; p = 0.03) and a greater improvement in the 6-minute walk distance (median change from baseline, 48.98 m vs. 23.80 m; p < 0.001). Adverse events including peripheral edema, headache, nasal congestion, and anemia were more common in the combination therapy group than either monotherapy.


Among participants with PAH who had not received previous treatment, initial combination therapy with ambrisentan and tadalafil resulted in a significantly lower risk of clinical failure events than the risk with ambrisentan or tadalafil monotherapy.


The study supports a rationale for initial combination therapy for PAH that needs to be validated in other trials. I was surprised that only 39% of those in the combination-therapy group achieved a satisfactory clinical response at 24 weeks, defined as an increase of 10% from baseline in the 6-minute walk distance, with a reduction in symptoms to, or maintenance of, WHO FC I or II and no events of worsening clinical condition. I was especially surprised since patients with a high risk for left ventricular diastolic dysfunction were excluded. Among the potential reasons include there is less benefit in those with CTD, and the WHO FC II have less actual or measurable benefit from the combination therapy.

Clinical Topics: Prevention, Hypertension

Keywords: Anemia, Connective Tissue Diseases, Disease Progression, Edema, Headache, Hypertension, Natriuretic Peptide, Brain, Phenylpropionates, Primary Prevention, Pyridazines

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