Triple and Double Therapy Prove Equal for PAH

Both dual-combination and triple-combination oral therapy cut pulmonary vascular resistance (PVR) in patients with newly diagnosed pulmonary arterial hypertension (PAH), although the triple-combo regimen failed to meet the primary endpoint of the TRITON trial.

In the phase IIIb study, at week 26, both treatment strategies reduced PVR compared with baseline by 54% and 52%, respectively, with no significant difference between groups (ratio of geometric means: 0.96, 95% CI 0.86 to 1.07, P=0.42), reported Kelly M. Chin, MD, of UT Southwestern Medical Center in Dallas, and co-authors.

However, risk for disease progression to the end of the main observation period was reduced with initial triple versus initial double therapy (hazard ratio 0.59, 95% CI 0.32 to 1.09) based on an exploratory analysis, they wrote in the Journal of the American College of Cardiology, though they noted that this finding should be interpreted with caution.

“While the study’s primary endpoint was not met, we observed a signal of reduced risk of disease progression in the initial triple oral combination therapy group as compared to the initial double oral therapy group,” co-author Nazzareno Galiè, MD, of the University of Bologna in Italy, told Businesswire. “This signal requires further evaluation to enhance our knowledge in the PAH field.”

Still, TRITON has been on a winning streak since results began rolling out across multiple platforms, such as the European Heart Journal and the Journal of Heart and Lung Transplantation, and the 2020 European Society of Cardiology virtual congress. Chin shared the results in a poster presentation at the 2020 American Thoracic Society virtual meeting.

“A unique feature of the study was that all patients were eligible to continue long-term blinded follow-up through the [end of main observation period], even if they had already discontinued one or study medications or had had a disease progression event,” explained Chin in a Pulmonary Vascular Research Institute presentation. The end of the main observation period was defined as the time at which the last patient randomized completed the week 26 visit.

The multicenter TRITON trial evaluated initial triple oral therapy—with macitentan (Opsumit), tadalafil [Cialis), and selexipag [Uptravi)—versus initial double oral therapy—macitentan, tadalafil, and placebo—in newly diagnosed, treatment-naive patients with PAH. The primary endpoint was change in PVR at week 26.

Secondary endpoints included change from baseline to week 26 in 6-minute walk distance (6MWD) and change from baseline to week 26 in N-terminal pro B-type natriuretic peptide (NT-proBNP) levels.

Treatment-naive PAH was confirmed by right heart catheterization within 6 months prior to randomization. Three-fourths of the 247 patients were female with a mean age of 51.9, and 85% were White. More than half were from North America, 46.6% had idiopathic PAH, and 34.4% had connective tissue disease-associated PAH.

Both study groups saw some patients withdraw prior to the endpoint, as well as deaths (two in the triple group; three in the double group), loss to follow-up, and patient or physician decision to stop therapy.

Right heart catheterization and other assessments were performed at week 26, after which patients continued follow-up in a blinded manner until the end of the main observation period, up to 3.1 years, with a mean follow-up duration for both groups of around 76 weeks.

The author reported that all patients who received triple combo therapy, and nearly 97% in the double group, experienced adverse events (AEs), such as headache, nausea, and diarrhea, and the majority of these AEs were deemed treatment emergent.

In a July 2020 YouTube presentation pre-TRITON reveal, Jeffrey Sager, MD, director for the Cottage Pulmonary Hypertension Center in Santa Barbara, California, highlighted other landmark studies for combination therapy in PAH, such as SERAPHIN, GRIPHON, and AMBITION trials.

“One of the big issues we deal with is the side effects because the more medications you have, you harder it is to deal with the side effects… in GRIPHON, 76% of patients experienced severe headache, 55% with diarrhea, and these are things that you have to manage,” he said. The same holds true for AMBITION, in which “the side effect profile is a challenge. You’ve got to anticipate the peripheral edema, the headache, and you’ve got to warn and counsel the patients.”

But Sager issued a warning about upfront triple combo therapy, comparing it to a triple axel jump in figure skating. “A triple axel is a beautiful thing to watch when performed perfectly well; executed well, it really looks wonderful,” he said, but that same move can be very dangerous when done by someone who isn’t a trained figure skater.

“And that’s why I warn providers who are giving [upfront triple combo therapy] to patients with PAH, sometimes they have so many side effects, and it’s hard to figure out ’Is that worsening heart failure? Is that a side effect of the medication? Is the edema from heart failure?’ You really need the experience and understanding to give patients that triple therapy,” Sager said, adding that patient-related issues also need to be considered, such as likely adherence to triple therapy, potential for loss to follow-up, cost of a multi-medication regimen, and finally the “manpower needed to get triple [therapy] approval in today’s insurance world.”

Chin and co-authors reported that at week 26, 6MWD increased from baseline by 55.0 m for initial triple therapy and 56.4 m for initial double therapy. NT-proBNP was 0.26 (95% CI 0.21 to 0.33) for a 74% reduction for initial triple therapy, and 0.25 (95% CI 0.20 to 0.32), for a 75% reduction for initial double therapy.

Also, in the initial triple therapy group, 13% had a first disease progression event versus 21.8% in the initial double therapy group, the authors reported, explaining that in “a time-to-event analysis, the hazard ratio for initial triple versus initial double therapy for the occurrence of a first event was 0.59 [95% CI 0.32 to 1.09].” By month 30 of follow-up, this correlated to 41% reduction is risk of disease progression with initial triple oral versus initial double oral combination therapy.

Chin’s group noted that this difference was driven by hospitalizations for worsening PAH, which occurred as the first event in 8.1% in the initial triple therapy group versus 15.3% in the initial double therapy group, and by all-cause deaths, with no deaths occurring as a first event in the initial triple therapy group versus 3.2% in the initial double therapy group.

Study limitations included the fact that analyses of disease progression and mortality were either exploratory, because of the testing hierarchy, or their post hoc nature. Also, the study was not event driven or powered to assess long-term outcome.

In an editorial comment accompanying the study, Jane A. Leopold, MD, of Brigham and Women’s Hospital in Boston, pointed out that TRITON did not answer one important question—Is there “a direct benefit of triple- versus double agent combination therapy on 2 determinants of PAH-associated clinical outcomes: RV function and RV–pulmonary artery (PA) coupling.”

She noted that cardiac imaging studies were not done in TRITON, and as “the effects of modest decreases in PVR of RV structure and function are not predictable, imaging the right heart becomes imperative… RV-PA coupling, although hard to assess, can be calculated from contemporaneous right heart catheterization and cardiac [MRI].”

However, Leopold added that “[t]he signal of reduced risk for disease progression and the absence of alarming safety issues for simultaneous triple combination therapy is supportive of further investigation.”

In a 2021 American Journal of Managed Care article, Stormi Gale, PharmD, of the University of Maryland School of Pharmacy in Baltimore, stated that “Current guidelines make no specific mention of upfront triple combination therapy. Limitations of current evidence include lack of robust study designs and heterogenous nature of therapies evaluated (i.e., oral vs parenteral). Special consideration should be given to patient preference in this setting, given the overwhelming nature of a new PAH diagnosis and the implications for adjusting to multiple new therapies, particularly as this relates to parenteral therapy. Given the limited data available, the role of this strategy remains unclear but may be considered for specific patients (i.e., those with high-risk features willing and able to tolerate triple combination therapy).”

1. Three-drug versus two-drug therapy for newly diagnosed pulmonary arterial hypertension (PAH) showed no significant differences in pulmonary vascular resistance between the groups after 26 weeks of treatment.

2. Exploratory analyses suggested a possible 41% reduction in risk of disease progression with initial triple versus initial double therapy.

Shalmali Pal, Contributing Writer, BreakingMED™

Cat ID: 195

Topic ID: 89,195,730,914,192,195,912,925