Triplet Therapy for PAH May Reduce Disease Progression vs Doublet Therapy


New data on treatment for newly diagnosed pulmonary arterial hypertension (PAH) show initial treatment for the progressive disease that includes macitentan has potential to reduce risk of disease progression.

Patients with newly diagnosed pulmonary arterial hypertension (PAH) who have yet to initiate treatment may find subsequent benefit in initial therapy with a triple- vs a double-drug combination, new data from the multicenter, double-blind, randomized phase 3b TRITON trial show.

This, and other findings, were recently published in Journal of the American College of Cardiology.

Oral triplet therapy with macitentan, tadalafil, and selexipag was compared with doublet therapy of macitentan, tadalafil, and placebo among treatment-naive patients, because “combination therapy to target multiple pathways is an essential part of PAH management [and] patients receiving double oral therapy, including initial double therapy, continue to experience PAH progression, providing a rationale for more intensive treatment.”

Previous studies, the authors added, have also shown initial triplet therapy to improve hemodynamic status, functional capacity, morbidity, and mortality. Participants in this study (aged 18 to 75 years) were randomized 1:1 to initial triple (n = 123) or double (n = 124) therapy by 28 days after study screening and had to have PAH confirmed in the 6 months leading up to this, a 6-minute walk distance (6MWD) of at least 50 meters, and pulmonary vascular resistance (PVR) of at least 6 WU; they were followed until week 26 for the last randomized patient.

The study regimens were the following:

  • Day 1 once-daily doses of 10-mg macitentan and 20-mg tadalafil
  • Days 5 to 11: once-daily doses of 10-mg macitentan/40-mg tadalafil, the latter increased according to tolerability
  • Days 12 to 18: the days 5-to-11 regimen plus twice-daily 200-mcg selexipag or placebo, which was increased weekly 200-mcg twice-daily through week 12 until the maintenance dose was achieved (range, 200-1600 mc twice daily)

Measurements of concern were right heart catheterization (screening, week 26), World Health Organization functional class, 6MWD, N-terminal pro–brain natriuretic peptide (NT-proBNP; screening, weeks 12 and 26, every 6 months thereafter, end of main observation period, end of all study treatments).

Over similar median follow-up periods—77.6 weeks for the triple-therapy group and 75.8 weeks for the double-therapy group—by week 26, the primary end point of change in pulmonary vascular resistance (PVR) was a drop of 54% for the triplet regimen and 52% for the double regimen. Also at week 26 for the secondary end points, increases of 55 and 56.4 meters were seen, respectively, for the triplet and doublet regimens, “while the geometric mean for the ratio of baseline to week 26 NT-proBNP” was 0.26, or a 74% reduction, and 0.25, or a 75% reduction.

Additional results show:

  • 67% more patients in the double-regimen group had a first disease progression event (21.8% vs 13.0%)
  • 15.3% of the double-regimen cohort vs 8.1% of the triple-regimen were hospitalized for worsening PAH as a first event
  • 4.3% vs none, respectively, had an all-cause death as the first event

Accounting for premature treatment discontinuation, a post hoc sensitivity analysis showed almost twice the amount of patients in the double-regimen group had a first disease progression event compared with the triple-regimen group—25 vs 14, respectively—for a 41% overall reduced risk of first disease progression event from triplet therapy. Nine and 2 patients, respectively, died.

The most common adverse events among all patients were headaches, diarrhea, and nausea, and they were more common in the triple-regimen group.

Despite the numbers being slightly better for the triple-regimen group, especially for PVR change, and that marked baseline improvements were seen for hemodynamic status, NT-proBNP, and functional parameters, the authors deemed the differences not significant.

Still, they believe their findings hold merit.

“Exploratory and post hoc analyses on long-term outcomes suggest a signal for reduced risk for disease progression with initial triple versus initial double oral therapy,” they concluded. “Furthermore, previous data showed that initial double oral therapy slows PAH progression compared with monotherapy. Our data build on these by suggesting that initial triple oral therapy may add incremental benefit over initial double therapy for further delaying disease progression.”


Chin KM, Sitbon O, Doelberg M, et al.Three- versus two-drug therapy for patients with newly diagnosed pulmonary arterial hypertension.J Am Coll Cardiol. 2021;78(14):1393-1403. doi:10.1016/j.jacc.2021.07.057

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