First-line combination therapy with ambrisentan and tadalafil cut the rate of clinical events in pulmonary arterial hypertension (PAH) by half, compared with monotherapy using either drug, in an international phase 3-4 clinical trial reported online Aug. 27 in the New England Journal of Medicine.
Ambrisentan, a selective endothelin-A-receptor antagonist, and tadalafil, a phosphodiesterase type 5 inhibitor, target different intracellular pathways known to have dysfunctional signaling in PAH, so researchers expected them to have an additive effect when combined. The study findings support the rationale of targeting multiple affected pathways early in the course of PAH, rather than following the traditional approach of sequentially adding newer agents to established background therapy, said Dr. Nazzareno Galie of the department of experimental, diagnostic, and specialty medicine, University of Bologna (Italy), and his associates.
Dr. Nazzareno Galie
The 4-year, industry-sponsored trial involved 500 adults treated at 120 medical centers in 14 countries for PAH with World Health Organization functional class II or III symptoms. It included patients whose disorder was idiopathic; hereditary; or associated with connective tissue disease, drugs or toxins, stable HIV infection, or repaired congenital heart defects.
The mean age of participants was 54.4 years, and 78% were women. The mean pulmonary artery pressure was 48.7 mm Hg, and mean 6-minute walk distance was 353 m at baseline. A total of 253 patients were randomly assigned to receive oral, once-daily combination therapy, 126 to receive ambrisentan plus placebo, and 121 to receive tadalafil plus placebo. They were assessed at monthly intervals during the 24-week treatment period and were allowed to continue therapy indefinitely. The mean duration of use of the study medication was 517 days. Patients were followed up a final time 1 month after taking their last dose of study medication.
The primary efficacy endpoint was the first event of clinical failure, which was a composite of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term treatment response. Only 18% of the combination-therapy group reached this endpoint, compared with 34% of the ambrisentan group, 28% of the tadalafil group, and 31% of the pooled-monotherapy group. The hazard ratios for the primary endpoint were 0.50 for the combination therapy versus pooled monotherapy, 0.48 for combination therapy versus ambrisentan alone, and 0.53 for combination therapy versus tadalafil alone.
This treatment benefit was mainly driven by one component of the combined endpoint: The rate of hospitalization for worsening PAH was three times higher with the two monotherapies (12%) than with combination therapy (4%). Improvement in the secondary endpoints of change in N-terminal pro–brain natriuretic peptide level, the percentage of participants with a satisfactory treatment response, and change in 6-minute walk distance all significantly favored the combination therapy, Dr. Galie and his associates said (N Engl J Med. 2015 Aug 27. doi: 10.1056/NEJMoa1413687).It is important to note, however, that “despite improvements in a variety of factors with combination therapy, we found no significant difference in WHO functional class among the study groups at week 24,” they wrote.
The combination of ambrisentan and tadalafil produced more adverse effects than either monotherapy, but the rate of discontinuation of a study drug and the rate of serious adverse events were similar across the three study groups. The most frequent adverse effects were peripheral edema, headache, nasal congestion, and anemia.
The AMBITION study was funded by Gilead Sciences and GlaxoSmithKline, which designed the trial, collected and analyzed the data, and wrote the report in conjunction with the authors. Gilead Sciences, GlaxoSmithKline, and Eli Lilly provided the study drugs. Dr. Galie reported receiving grants and personal fees from GlaxoSmithKline, Actelion, Bayer, and Pfizer; his associates reported ties to numerous industry sources.