Ambrisentan-tadalafil combination provides benefit in pulmonary arterial hypertension
First-line combination therapy with ambrisentan plus tadalafil provided clinical benefits for patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), particularly systemic sclerosis-associated PAH (SSc-PAH), according to a post hoc analysis of the AMBITION* trial.
The primary analysis set comprised 500 treatment-naïve patients who had WHO functional class II/III PAH at baseline. A total of 187 patients diagnosed with CTD-PAH, 118 of which were SSc-PAH cases, were randomized to once-daily ambrisentan (10 mg, n=44), tadalafil (40 mg, n=40), or ambrisentan (10 mg) plus tadalafil (40 mg, n=103).
A reduced risk of clinical failure was observed among patients on combination therapy compared with pooled monotherapy, be it patients with CTD-PAH (hazard ratio [HR], 0.43, 95 percent confidence interval [CI], 0.24–0.77) or SSc-PAH (HR, 0.44, 95 percent CI, 0.22–0.89). [Ann Rheum Dis 2017;76:1219-1227]
Compared with pooled monotherapy, combination therapy also resulted in greater mean reduction in NT-proBNP** (CTD-PAH, -60.4 percent vs -43.1 percent and SSc-PAH, -62.8 percent vs -38.4 percent) and increased median 6-minute walking distance (6MWD; CTD-PAH, +42.0 vs +24.3 m and SSc-PAH, +40.9 vs +12.2 m) at week 24.
6MWD could be a useful indicator of treatment response in the SSc-PAH population despite limited improvement with monotherapy, said the researchers.
The most common adverse events associated with combination therapy reported in the CTD-PAH and SSc-PAH groups were peripheral oedema (47 and 45 percent, respectively), headache (33 and 28 percent), and diarrhoea (29 and 28 percent).
Although the study protocol was adjusted to exclude postcapillary pulmonary venous hypertension, [N Engl J Med 2015;373:834-844] evaluation of all randomized subjects receiving the study drug revealed similar results, with risk reductions in both CTD-PAH (HR, 0.48) and SSc-PAH populations (HR, 0.46).
“[E]xcluding patients who failed to meet the revised inclusion criteria had limited impact on the outcome,” said the researchers.
SSc-PAH has a relatively poor prognosis and has been the leading cause of CTD-PAH. [Ann Intern Med 2000;132:425-434; Ann Rheum Dis 2006;65:1336-1340; J Rheumatol 2007;34:2417-2422] The present findings thus provide informative insight on the management of patients with CTD-PAH, noted the researchers.
“These results support the notion that CTD-PAH, particularly SSc-PAH, may need a more aggressive treatment regimen to see similar benefits to patients with [idiopathic PAH] … An aggressive approach … with initial combination therapy may improve outcomes and exercise capacity as opposed to treatment with monotherapy,” said the researchers.