Methods:
TRITON was a multicenter, double-blind, randomized, placebo-controlled phase 3b study investigating triple up-front oral therapy compared with double up-front oral therapy in pulmonary arterial hypertension (PAH).

Patients were 18-75 years of age with group 1 PAH diagnosed within 6 months of study entry. Included PAH subgroups were idiopathic, heritable or drug/toxin induced, connective tissue disease (CTD-PAH), HIV infection and corrected congenital heart disease. All patients were PAH therapy naïve and had a pulmonary vascular resistance by right heart catheterization of at least 6 Woods units. Patients were randomized 1:1 to initial triple therapy (tadalafil, macitentan and selexipag) or initial double therapy (tadalafil, macitentan and placebo). The studies' primary endpoint, change in pulmonary vascular resistance (PVR), and most secondary endpoints were assessed at week 26. Patients then continued in their assigned groups until the last patient had reached week 26, resulting in a median follow-up of 1.5 years (range up to 3.1 years). The time to clinical worsening secondary endpoint was measured over this entire main observation period.

Results:
A total of 247 patients were randomized to initial triple therapy (N=123) versus initial double therapy (N=124), and most patients had idiopathic (47%) or CTD-PAH (34%). At week 26, PVR decreased by 54% with initial triple therapy and by 52% with initial double therapy, for a treatment effect ratio of 0.96 (95% CI: 0.86-1.07; P = 0.42). There were no between group differences seen for the secondary endpoints measured at 26 weeks, including 6-min walk distance (6MWD), NT-proBNP, and other hemodynamic measures. For time to clinical worsening, a secondary endpoint measured over the entire main observation period, 16 (13%) patients in initial triple therapy and 27 (21.8%) patients in initial double therapy group had a first disease progression event; HR 0.59 (95% CI: 0.32-1.09). This included fewer hospitalizations (10 [8%] vs. 19 [15%]) and fewer deaths (0 vs. 4 [3%]) in the triple therapy group. In an exploratory analysis looking at all events including recurrent hospital admissions, there were 31 events in 16 patients in the initial triple therapy group and 67 events in 27 patients in the initial double therapy group (rate ratio 0.39 [95% CI 0.15-1.00]).

All patients in the initial triple therapy group and 96.9% in double therapy group experienced at-least one adverse events (AE). Most common treatment-emergent AEs were headache, diarrhea, nausea, and peripheral edema. Except for peripheral edema, all other AEs were more frequent in triple therapy group. Serious AEs were experienced in 42.9% of initial triple therapy and 31.5% in double therapy. There were 19 (16 %) patients who discontinued selexipag and 17 (14.2%) patients who discontinued placebo due to AEs.

Conclusions:
Although both the initial triple and initial double therapy groups had marked improvement in hemodynamics including PVR, 6MWD and NT-proBNP levels at week 26 compared with baseline, there were no significant between-group differences. However, composite time to first disease progression analysis signaled a possible reduction in long-term disease progression in the triple therapy group, as compared with double therapy.

Perspective:
Currently approved therapies for PAH target the nitric oxide, endothelin, and prostacyclin pathways. In 2015, the AMBITION trial showed that an upfront combination therapy with tadalafil and ambrisentan lowered risk of clinical failure events as compared to either used as a monotherapy.¹ That same year in the GRIPHON clinical trial, selexipag was found to be superior to placebo in reducing the composite endpoint of death, PAH related hospitalization, or other PAH clinical worsening events, and consistent results were seen for patients receiving combination PAH background therapy with an ERA and PDE5 inhibitor.² These studies then brought up the natural follow-up question: if two drugs upfront are better than one, perhaps upfront triple therapy targeting all three pathways would be superior to upfront double therapy? The TRITON clinical trial studied this important question, but leaves the question incompletely answered.³

The discordance between the lack of short-term improvement in hemodynamics, 6MWD and NT-proBNP at 26 weeks versus a possible improvement in reducing longer-term disease progression events remains incompletely explained. Could the duration have been too short for these endpoints? Perhaps if the 26-week measures were remeasured over a longer period, then differences between the two groups might have emerged. Alternatively, as pointed out by Dr. Leopold in the editorial that accompanied this study, perhaps there were differences in post-treatment RV structure or function that would have been seen had the study included cardiac imaging endpoints.⁴ Right ventricular (RV) function, remodeling and RV-pulmonary artery (PA) coupling are important prognostic markers but do not correlate tightly with PVR, and it is plausible that differences in RV function and remodeling could help explain the triple therapy group's (possibly) lower disease progression rate.

Most importantly, the studies' discordant findings highlight the need for the use of clinically meaningful long-term endpoints outcomes when assessing novel therapies and novel therapeutic strategies in PAH. Prior meta-analyses have found only a modest relationship, at best, between short-term endpoints in PAH and long-term clinical events in PAH,⁵ though it was previously felt that this applied mainly to endpoints such as 6MWD, and not PVR.

Lacking definitive studies, what is best clinical practice in this area? Current guidelines and expert reviews recommend initial oral double combination therapy in most newly diagnosed low to intermediate risk PAH patients, with a residual role for monotherapy in certain situations.^6,7 Close, short-term follow-up is recommended, with escalation to triple therapy in patients with an inadequate initial response. While various triple therapy combinations are possible, the combination of an ERA, PDE5i and selexipag is the only triple oral combination note to have "received the highest recommendation and evidence" at this time, based primarily on the GRIPHON study.^2,7 Patients at greater risk at initial diagnosis as well as those failing oral therapies should be started on an intravenous or subcutaneous prostanoid, generally as a part of triple combination therapy. This recommendation is based on randomized controlled clinical trials of the parenteral prostanoids alone and as a part of double combination therapy,^8-11 and on greater hemodynamic improvement and better long-term outcomes with triple combination therapy with a parenteral prostanoid in observational studies.¹² Longer-term studies of therapeutic strategies are needed to fine-tune these recommendations.

References

1. Galie N, Barbera JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med 2015;373:834-44.
2. Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J Med 2015;373:2522-33.
3. 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;78:1393-1403.
4. Leopold JA. Initial triple pharmacotherapy in pulmonary arterial hypertension: is more necessarily better? J Am Coll Cardiol 2021;78:1404-1406.
5. Gabler NB, French B, Strom BL, et al. Validation of 6-minute walk distance as a surrogate end point in pulmonary arterial hypertension trials. Circulation 2012;126: 349-56.
6. Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: the joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015;46:903-75.
7. Galie N, Channick RN, Frantz RP, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. Eur Respir J 2019;53:1801889.
8. Barst RJ, Rubin LJ, Long WA, et al., A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-301.
9. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000;132:425-34.
10. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:800-04.
11. Simonneau G, Rubin LJ, Galie N, et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med 2008;149:521-30.
12. Boucly A, Savale L, Jais X, et al. Association between initial treatment strategy and long-term survival in pulmonary arterial hypertension. Am J Respir Crit Care Med 2021;204:842-54.

Clinical Topics: Congenital Heart Disease and Pediatric Cardiology, Dyslipidemia, Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Congenital Heart Disease, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Lipid Metabolism, Statins, Pulmonary Hypertension

Keywords: Tadalafil, Phosphodiesterase 5 Inhibitors, Nitric Oxide, Pulmonary Arterial Hypertension, Prognosis, Follow-Up Studies, Double-Blind Method, HIV Infections, Pulmonary Artery, Disease Progression, Cardiac Catheterization, Hospitalization, Edema, Vascular Resistance, Heart Defects, Congenital, Connective Tissue Diseases, Prostaglandins I, Hemodynamics, Endothelins, Prostaglandins, Headache, Hospitals, Nausea, Pharmaceutical Preparations

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