Initial PAH Therapy: Upfront Dual Oral Combination and Guideline Risk Stratification

"Initial PAH Therapy: Upfront Dual Oral Combination and Guideline Risk Stratification" takes up the question of how to choose a first regimen for a newly diagnosed patient.

Dr. McLaughlin asks Dr. Channick what shapes the initial treatment decision. He answers that every patient is different, so tolerability, adherence, and patient preference all matter. The standard approach, supported by strong data, is upfront dual oral therapy with an endothelin receptor antagonist and a PDE5 inhibitor for most patients who are not high risk. Those with heart failure or severe hemodynamic compromise may need parenteral therapy. He argues that follow-up matters more than the starting regimen, because clinicians must reassess quickly and add therapy when needed.

Dr. McLaughlin then asks Dr. Kim about the guideline documents, including the 2024 World Symposium recommendations and the European guidelines updated in September 2026. Dr. Kim values how the recent versions simplify decisions. Clinicians ask whether the patient presents in failure or at high risk, in which case rescue therapy is needed and is often parenteral, and everyone else receives oral combination therapy. He warns that clinicians can no longer rely on gestalt, because experience helps identify the sickest patients but only formal risk assessment reveals who is truly low risk. He urges listeners to stay current as guidance evolves.

Dr. McLaughlin summarizes that very high-risk patients receive upfront triple therapy including a parenteral prostacyclin, while all others receive upfront dual therapy. Dr. Channick reviews the evidence. The SERAPHIN trial tested add-on macitentan in patients on background PDE5 inhibitor therapy and was the first event-driven study to show long-term morbidity and mortality benefit. The AMBITION trial then tested upfront combination of an endothelin receptor antagonist and a PDE5 inhibitor and showed significant benefit on morbidity, mortality, and clinical improvement endpoints. He notes the results extend to other combinations within the two classes.

Up next, in "Fixed-Dose Combination Therapy in PAH: Simplifying Upfront Treatment," the experts discuss starting combination therapy in practice and the role of a single-tablet option.