First-line triple combo therapy shows potential in PAH
Adding selexipag to the double combination therapy of macitentan and tadalafil (triple combination) improved multiple outcomes in patients newly diagnosed with pulmonary arterial hypertension (PAH), results of the phase IIIb TRITON* trial showed.
Participants in this multicentre, double-blind trial were 247 patients aged 18–75 years with newly diagnosed, previously untreated PAH (up to 6 months prior). They were randomized 1:1 to receive initial triple oral therapy (selexipag-macitentan-tadalafil; mean age 52.2 years, 75.6 percent female, mean 23.9 days since PAH diagnosis) or double therapy (macitentan-tadalafil; mean age 51.6 years, 75.8 percent female, mean 19.8 days since PAH diagnosis). Patients received macitentan (10 mg QD) and tadalafil (20 mg QD, increased to 40 mg QD at day 8) from day 1, while selexipag (200 mg BID) or placebo was initiated at day 15 and uptitrated weekly in 200 mg BID increments, achieving individualized maintenance dose by week 12.
The study was unblinded at the end of the main observation period, the point when the last patient had completed the week 26 visit. During the double-blind period, patients on initial triple and double therapy had received treatment for a median 68.1 and 57.0 weeks, respectively. Overall, patients in the triple and double therapy groups were followed up for a median 77.6 and 75.8 weeks, respectively.
At baseline, mean 6-minute walk distance (6MWD) was 345 and 347 m in the triple and double therapy groups, respectively. PAH was primarily idiopathic/heritable and most patients were WHO** functional class III–IV.
Comparable efficacy with double therapy
At week 26, pulmonary vascular resistance (PVR) was reduced by 54 and 52 percent in the initial triple and double therapy groups, respectively, with no significant between-group difference (treatment effect ratio of geometric means, 0.96, 95 percent confidence interval [CI], 0.86–1.07; p=0.424). [ATS 2020, abstract 924]
At week 26, both groups experienced changes in 6MWD, again with no significant difference between the triple and double therapy groups (least squares [LS] mean change from baseline, 55.0 vs 56.4 m; LS mean difference, -1.4, 95 percent CI, -19.4 to 16.5; p=0.876). Likewise, there was a 74 and 75 percent reduction, respectively, in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, with no between-group difference (treatment effect ratio of geometric means, 1.03, 95 percent CI, 0.77–1.37; p=0.853).
A similar proportion of patients who received triple and double therapy did not experience worsening WHO functional class*** (99.2 percent vs 97.5 percent; odds ratio, 3.18, 95 percent CI, 0.32–31.82; p=0.326).
There was a greater, albeit nonsignificant, reduction in disease progression, assessed up to 7 days post-observation period, in the triple vs double therapy arm (risk reduction, 41 percent; hazard ratio, 0.59, 95 percent CI, 0.32–1.09; p=0.087). At 24 months, 85.2 and 74.0 percent of patients who received triple vs double therapy had not experienced disease progression. Common first disease progression events in the triple vs double therapy groups were hospitalization for worsening PAH (10 vs 19) and clinical worsening of PAH (5 vs 2).
Almost all patients experienced adverse events (AEs; 100.0 percent vs 96.9 percent [triple vs double therapy]), while serious AEs occurred in 42.9 and 31.5 percent, respectively. AEs led to treatment discontinuation in 16.0 and 14.2 percent, respectively, during the double-blind phase. The most frequent AEs (≥25 percent of patients) in the triple therapy group were headache (68.9 percent), diarrhoea (53.8 percent), and nausea (47.9 percent), and in the double therapy group, headache (60.6 percent), peripheral oedema (36.2 percent), and diarrhoea (31.5 percent). Eleven deaths occurred over the observation period, two and nine in the triple and double therapy groups, respectively.
What do the results say?
“In PAH, initial double oral combination therapy is recommended in newly diagnosed patients,” said the researchers.
“In the TRITON study of newly diagnosed PAH patients, haemodynamics, NT-proBNP, and functional capacity were markedly improved with initial triple oral and initial double oral therapy, with no difference between treatment strategies at week 26,” they noted.
“[Additionally,] exploratory analysis indicated a signal for improved long-term outcome with initial triple vs initial double therapy,” they said.