Benefit Confirmed for Combo Therapy in PAH-'Concrete, A-plus evidence' for better outcomes with tadalafil-ambrisentan

By Dr Deepu

Combination therapy with ambrisentan (Letairis) and tadalafil (Adcirca, Cialis) can significantly reduce the risk of clinical-failure events for pulmonary arterial hypertension (PAH) patients compared with either drug alone, according to complete results from a clinical trial now published in a major peer-reviewed journal.

Risk of first clinical failure -- defined as either death, hospitalization for worsening PAH, disease progression or unsatisfactory long-term clinical response to medication -- was reduced by half in the combination therapy group versus the two single therapy groups combined (hazard ratio 0.50; 95% CI 0.35-0.72; P<0.0001), Nazzareno Galiè, MD, of the University of Bologna, Italy, and colleagues reported in the New England Journal of Medicine.
Major findings from the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study were also presented earlier this year at the American Thoracic Society's annual meeting. The NEJM publication confirms and extends that report.

AMBITION was a randomized, double-blind, 14-center study that included 500 treatment-naïve patients with World Health Organization class II or III symptoms of PAH.

During the trial, patients were randomly assigned in a 2:1:1 ratio to receive either 10 mg of ambrisentan plus 40 mg of tadalafil, 10 mg of ambrisentan plus placebo, or 40 mg of tadalafil plus placebo once a day. A clinical failure event occurred in 46 of 253 patients (18%) in the combination therapy group, 43 of 126 patients (34%) in the ambrisentan monotherapy group and 34 of 121 patients (28%) in the tadalafil monotherapy group, for a total of 77 of 247 patients (31%) in the two monotherapy groups combined.

At 24 weeks, the combination therapy group had greater reductions from baseline in N-terminal pro-brain natriuretic peptide levels than the pooled monotherapy group (-67.2% vs. -50.4%; P<0.001). Those receiving combination therapy also had 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 6-minute walk distance (median change from baseline 48.98 m vs. 23.80 m; P<0.001).

"Most previous clinical studies that have investigated combination therapy for PAH have evaluated sequential add-on therapies," the authors wrote. "The AMBITION trial supports the rationale for targeting multiple pathways in pulmonary arterial hypertension and showed that early combination therapy can be beneficial."

Mean duration of use of a study medication was 517 days (550 in the combination therapy group and 484 in the pooled monotherapy group, P=0.03). Mean duration of study participation was 609 days (629 for combination therapy and 593 for pooled monotherapy, P=0.27). Sixty-four participants (13%) withdrew from the study before having a clinical failure event.

Peripheral edema, headache, nasal congestion and anemia were among the adverse events (AEs) that occurred more frequently in the combination therapy group than in either monotherapy group. Dizziness was more common with combination therapy than with tadalafil alone, and syncope was more common with tadalafil monotherapy than with the other groups. The most common AEs resulting in discontinuation of a study drug were peripheral edema and dyspnea; the most common serious AEs were worsening of PAH and pneumonia.

There were several limitations to the study, the authors noted, including finding no significant difference in WHO functional class among the study groups at week 24. In addition, they said, it isn't known whether the study findings can be extrapolated to other drugs in the same classes or whether initial combination therapy with drugs for other classes of approved therapies for PAH would produce similar results.