How is PAH Treatment and Management Changing?

Pulmonary arterial hypertension (PAH) treatment has advanced quickly in the last couple of years, especially with the recent approvals of macitentan and tadalafil (Opsynvi), the first single-tablet combination of macitentan and tadalafil, based on phase 3 A DUE data showing greater reductions in pulmonary vascular resistance than either drug alone, and sotatercept (Winrevair), a first-in-class activin signaling inhibitor cleared on the strength of the phase 3 STELLAR trial.1,2,3

Against that backdrop, a multidisciplinary panel of PH specialists convened for a case-based dinner discussion moderated by Stacy Mandras, MD, director of the pulmonary hypertension program at AdventHealth. The discussion arrived as upfront combination therapy—built on the decade-old AMBITION trial, which showed a 50% reduction in risk of clinical failure with upfront ambrisentan plus tadalafil compared with monotherapy—has become the default starting point for most newly diagnosed patients, leaving the panel to work through a newer and more layered question: how new treatments fits into escalation, de-escalation, and risk-based follow-up now that a third mechanism sits alongside endothelin, nitric oxide, and prostacyclin pathway drugs.4

The panel’s most animated exchanges centered on where sotatercept belongs relative to parenteral prostacyclin, which several specialists described as the only therapy in 25 years of PAH treatment consistently linked to hemodynamic normalization. Panelists disagreed on sequencing: some start sotatercept only after a patient is already on a prostacyclin, arguing the prostacyclin provides faster symptom relief while sotatercept’s effect builds over weeks, while others said sotatercept has let them delay or avoid the “misery” of pump therapy in appropriately selected intermediate-risk patients. Nearly everyone agreed that shared decision-making, not the algorithm alone, increasingly decides which pathway a given patient takes, since patient tolerance for pill burden, injections, and continuous infusion varies widely. The panel was similarly split on risk-assessment tools, with several specialists favoring the US-based REVEAL registry for its vital-sign and biomarker granularity and others using both REVEAL and the European ESC/ERS framework in parallel, agreeing only that consistency in whichever tool is chosen matters more than which one is used.

Risk Assessment Tools Guide Therapy Intensification

On sequencing after diagnosis, panelists described a shift toward triple and even quadruple combination therapy for high-risk patients, drawing an analogy to multidrug HIV therapy, and cited persistent gaps in evidence for patients with mixed PAH-COPD physiology, where distinguishing disease progression from decompensation of the other condition remains, in one panelist’s words, “somewhat of a secret within the community.”

"For me personally, my most important visit is at the time of diagnosis. That's the time where I'm connecting with the patient, having them understand as best as I can their disease state, and then telling them what their future holds, the panelist said.

The panel closed on unmet needs, calling out the absence of head-to-head trials between agents, uncertainty about de-escalating off prostacyclin once sotatercept is added, and a persistent evidence gap in identifying which patients with overlapping cardiopulmonary disease will safely tolerate vasodilator escalation.

References

1. FDA Approves Sotatercept (Winrevair) for Pulmonary Arterial Hypertension. HCPLive. Published March 26, 2024. Accessed September 2, 2026. https://www.hcplive.com/view/fda-approves-sotatercept-winrevair-for-pulmonary-arterial-hypertension

2. FDA Expands Indication for Merck’s Winrevair in Pulmonary Arterial Hypertension. Pharmaceutical Executive. Published October 28, 2025. Accessed September 2, 2026. https://www.pharmexec.com/view/fda-merck-winrevair-pulmonary-arterial-hypertension

3. FDA Approves Single-Tablet Macitentan, Tadalafil Combination (Opsynvi) for Pulmonary Arterial Hypertension. HCPLive. Published March 22, 2024. Accessed September 2, 2026. https://www.hcplive.com/view/fda-approves-single-tablet-macitentan-tadalafil-combination-opsynvi-pulmonary-arterial-hypertension

4. Galiè N, Barberà JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension. N Engl J Med. 2015;373(9):834-844.