Initial combination therapy with ambrisentan (AMB) and tadalafil (TAD) in treatment naïve patients with pulmonary arterial hypertension (PAH): Efficacy and safety in the AMBITION study intent to treat (ITT) population

Introduction: AMBITION was an event driven trial investigating efficacy and safety of initial combination (COMB) therapy compared with monotherapy in a heterogeneous PAH patient population. Aims and objectives: We present the results from the entire study population (ITT). Methods: 605 patients were randomized to COMB (n=302), AMB (n=152) or TAD (n=151) monotherapy. Patients were categorized into two populations based on revised eligibility criteria in a protocol amendment; those that met revised criteria (Primary Analysis Set=PAS, n=500), and those that did not mainly due to the presence of cardiovascular comorbidities (Ex-PAS, n=105). The primary endpoint was time to clinical failure (TTCF; all-cause death, hospitalization for worsening PAH, disease progression and unsatisfactory long term clinical response). Secondary endpoints at Week 24 included NT-proBNP, % achieving satisfactory clinical response, 6MWD, WHO FC, and Borg Score. Results: The TTCF was significantly reduced with COMB vs. pooled monotherapy (HR 0.532, 95% CI: 0.385, 0.733; p<0.0001) and vs. each monotherapy (AMB, p=0.0002; TAD, p=0.0023). A reduction in PAH hospitalizations drove the treatment effect. The primary outcome in the Ex-PAS population showed a similar trend. Results for secondary endpoints will be presented. Peripheral oedema, headache, nasal congestion, and anaemia were more common in COMB than either monotherapy. Conclusion: Initial combination therapy (AMB + TAD) significantly reduced the risk of a clinical failure event compared with monotherapy in the AMBITION ITT population.