Upfront Combination Therapy: Growing the Case to Get Ahead of Pediatric Pulmonary Arterial Hypertension
Abstract
Pulmonary arterial hypertension (PAH) is a rare, life-limiting disease marked by progressive remodeling of the pulmonary vascular bed that affects patients of all ages (1). Over the past two decades, the advent and increased use of pulmonary-specific vasodilator therapies has improved lung transplant–free survival in children with PAH (2–4). These therapies modulate vasoactive signaling to relax the pulmonary arterial bed through three distinct pathways: the nitric oxide, endothelin, and prostacyclin pathways (5). In recent years, much research has focused on optimization of timing, dosing, and defining the advantages of combination therapy in the treatment of PAH (6). Despite these improved therapeutic opportunities, the timing of drug initiation, transition, dosing, and benefits of additive therapy specific to the pediatric population remains incompletely understood. Credence for early aggressive pulmonary vasodilator therapy in patients with PAH started with clinician experience and observational data but was subsequently propelled by adult studies suggesting beneficial response (7). Over 15 years ago, the small BREATHE-2 (Bosentan Randomized trial of Endothelin Antagonist Therapy for PAH) trial was the first upfront combination randomized clinical trial, using intravenous epoprostenol and bosentan in some subjects and finding a nonsignificant improvement in hemodynamics for those on combination therapy (8). In 2015, the AMBITION (Ambrisentan and Tadalafil in Patients…
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
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