Initial triple therapy vs. double may improve outcomes in newly diagnosed PAH: TRITON

In patients with newly diagnosed pulmonary arterial hypertension, initial triple oral therapy, compared with double therapy, both improved hemodynamics, NT-proBNP and functional capacity, with no difference between strategies at 26 weeks.

Kelly M. Chin, MD, associate professor of internal medicine and pulmonary critical care medicine at University of Texas Southwestern Medical Center, and colleagues reported results of TRITON, a randomized, double-blind, placebo-controlled, multicenter, phase 3b study. study was designed to assess the safety and efficacy of initial triple oral therapy with selexipag (Uptravi, Actelion Pharmaceuticals), macitentan (Opsumit, Actelion) and tadalafil (n = 123) compared with initial double oral therapy with macitentan and tadalafil (n = 124) in treatment-naive patients with PAH. Dual therapy with macitentan 10 mg per day and tadalafil 20 mgper day was administered at randomization. The tadalafil dose was increased to 40 mg per day on day 8. Double-blinded selexipag or placebo were initiated at 200 g twice daily on day 15, then uptitrated weekly for up to 12 weeks to reach the individualized maintenance dose, according to the study details.

Patients enrolled had a PAH diagnosis within the previous 6 months. Three-quarters of the patients were women and the mean age was 52 years. Idiopathic PAH and connective tissue disease PAH were the most common PAH classifications. Baseline pulmonary vascular resistance was 12 Wood units and patients presented with reduced cardiac index.

Primary endpoint was change in pulmonary vascular resistance at 26 weeks.

At 26 weeks, the researchers reported a marked decrease in pulmonary vascular resistance of 54% in the initial triple therapy group vs. 52% in the double therapy group, with no significant difference between the two treatment strategies (P = .424).

The researchers also observed improvements in secondary endpoints at 26 weeks, which they noted should be interpreted as exploratory, including large increases in NT-proBNP (74% reduction with triple therapy vs. 75% reduction with double therapy; P = .853), improvement in 6-minute walk distance (+55 m with triple therapy vs. +56.4 m with double therapy; P = .876) and hemodynamic parameters such as mean pulmonary arterial pressure and cardiac index. Researchers observed no worsening in functional class at week 26. Again, there was no difference between the treatment groups in these secondary outcomes.

“Exploratory analysis indicated a signal for improved long-term outcome with initial triple oral vs. initial double oral therapy,” Chin said.

Risk for disease progression decreased by 41% in the initial triple therapy group vs. the initial double therapy group (HR = 0.59; 95% CI, 0.32-1.09; P = .087). A disease progression event occurred in 13% of the initial triple therapy group compared with 21.8% of the initial double therapy group.

patients experienced at least one adverse event with the initial triple therapy group. Adverse events that occurred in more than 25% of patients included headache, diarrhea, nausea, pain in extremity, jaw pain and vomiting. Two (1.7%) patients in the initial triple therapy group and nine (7.1%) in the initial double therapy group died during the study period.

“The nature of the adverse events reported were expected in this patient population and consistent with the known safety profile of the study medications,” Chin said during a prerecorded presentation at the American Thoracic Society Virtual meeting.

Chin noted that TRITON is the first randomized controlled clinical trial to evaluate the efficacy and safety of initial triple vs. double oral combination therapy in this patient population.

Reference:

Chin KM, et al. Am J Respir Crit Care Med. 2020;201:A2928.