PAH in 2026: Algorithm Shifts and Real-World Gaps

The therapeutic landscape for pulmonary arterial hypertension (PAH) has undergone more change in the past 4 years than in the preceding decade. The 2022 ESC/ERS guidelines formalized upfront dual combination therapy with an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor as the standard of care for low- and intermediate-risk patients, a risk-stratified four-strata follow-up model for treatment escalation decisions, and a revised hemodynamic definition of PH — lowering the PVR threshold from 3 to 2 Wood Units — that has meaningfully expanded the diagnosable and treatable population.¹

The 7th World Symposium on Pulmonary Hypertension, convened in 2024, further refined the treatment algorithm to formally incorporate activin signaling inhibition as an escalation option at intermediate- and high-risk follow-up, and to position oral and inhaled prostacyclin agonists as a distinct intermediate-risk escalation pathway, while reserving parenteral prostacyclin primarily for high-risk presentations and patients failing to achieve low-risk status on maximal oral therapy.² Since 2022, 3 additional therapies have received regulatory approval: sotatercept (Winrevair; Merck), the first activin signaling inhibitor, supported by the STELLAR and ZENITH trials; Opsynvi (macitentan/tadalafil; J&J), a fixed-dose combination that simplifies upfront dual therapy to a single once-daily tablet; and sildenafil 80 mg 3-times-daily as a higher-dose PDE5i option.³ Together, these developments have not merely expanded the pharmacopeia — they have shifted the fundamental logic of how, when, and in what sequence PAH therapy is applied.

Against this backdrop, HCPLive convened a panel of PAH specialists — pulmonologists, advanced heart failure cardiologists, and PH program directors — from the Columbus, Georgia region and surrounding Alabama and Georgia communities for an in-depth dinner roundtable discussion. The forum was moderated by Hunter Champion, MD, Southeastern Cardiology, a PAH specialist with extensive experience in cardiopulmonary exercise testing, exercise right heart catheterization, and long-term cohort outcomes in PAH, and included advanced heart failure cardiologists, pulmonologists, and PH specialists from academic-affiliated and community practices across the region. The panel's composition — spanning high-volume PH centers, cardiology practices managing predominantly combined pre-post disease, and community pulmonologists managing patients who cannot or will not travel to centers of excellence — produced a discussion as shaped by 25 years of collective clinical experience and regional demographics as by published trial data. The discussion centered on 4 areas: how the updated treatment algorithm is being implemented in practice, the evolving role of prostacyclin therapy in the combination era, real-world monitoring approaches, and the persistent access and adherence barriers that govern what patients actually receive.

Prostacyclin's Changing Role: De-escalation, High-Dose Inhaled Therapy, and Transition Strategies

The panel reached unanimous agreement on a finding that would have seemed unlikely even 3 years ago: prostacyclin therapy is moving downward in the PAH treatment algorithm — in intensity, route, and timing of initiation — driven by the accumulating experience with newer agents, higher achievable inhaled doses, and the first clinical signals of meaningful de-escalation in patients who respond dramatically to activin signaling inhibition. Several panelists described what they termed a "new dual therapy": a PDE5 inhibitor or sGC plus an activin signaling inhibitor as the backbone, with the ERA introduced as a third agent — inverting the traditional sequence in which the ERA/PDE5i combination forms the immovable upfront foundation.

For patients who cannot tolerate subcutaneous injection, the fixed-dose Opsynvi (macitentan 10 mg/tadalafil 40 mg) has simplified the upfront combination to a single once-daily tablet, with 1 panelist noting that Opsynvi's 90-day free-drug program has been "a big game changer" for initiating dual therapy without prior authorization delay. Champion cited cardiac index as a primary driver of his own escalation decisions: patients with a CI between 1.6 and 2.4 — approximately 35% to 40% of his panel — are moved more aggressively toward earlier escalation or broader upfront therapy rather than waiting for symptomatic progression. Inhaled treprostinil has also evolved: panelists described routinely titrating patients to 2 to 3 cartridges of Yutrepia daily, achieving what Champion characterized as legitimate IV-equivalent hemodynamic exposure, and several described successful IV-to-inhaled transitions in patients who were previously considered too complex for that approach. The key criteria for prostacyclin de-escalation — discussed by multiple panelists as now an active rather than theoretical strategy — included 6 to 12 months of stability, normalization or near-normalization of RV size and function on echocardiography, a favorable NT-proBNP trend, and repeat right heart catheterization before any dose reduction. As one panelist summarized the group's direction: "I definitely think there's always going to be a place for prostacyclins. But it's certainly moving down a little bit."

Risk Stratification, Monitoring Tools, and What Echoes Don't Capture

Risk stratification was described as a multiparametric, every-visit exercise — with no single tool adequate on its own and no panelist relying exclusively on any 1 calculator. Champion described using the French registry for rapid clinical gestalt (3 parameters, no math) and REVEAL Lite when a more comprehensive objective score is needed, noting that heart rate carries particular prognostic weight as a standalone marker and is incorporated into REVEAL Lite but not the French registry. The 4-strata ESC/ERS model was acknowledged as clinically useful at follow-up, consistent with the 7th WSPH algorithm's endorsement of more granular risk categorization at reassessment visits. A common clinical challenge surfaced repeatedly: echo-risk score discordance, in which a patient scores as low-risk on REVEAL but presents with persistent RV enlargement on echocardiogram.

The panel's consensus was to manage toward the worse of the 2 signals — echoes showing meaningful RV dilation should push escalation decisions even when a composite score suggests stability. Echocardiograms were performed every 3 months for the first year by most panelists, with Champion cautioning that guideline language must preserve a 3-to-6-month window explicitly, because payers will apply the most restrictive reading of any flexibility in the language and restrict coverage to annual imaging regardless of severity.

Champion described using high-throughput sub-maximal CPET — a SHAPE-validated system running 15 to 18 tests per day — as a monitoring tool that adds signal unavailable from echo or 6MWT alone: patients with apparently normalized RV systolic pressure on echo who still show impaired pulmonary blood flow augmentation on CPET represent a group in whom he continues therapy despite superficially reassuring imaging. Right heart catheterization was reserved for major treatment decisions and clinical worsening events rather than used for routine surveillance, with the panel broadly agreeing that CPET and echo together provide an adequate monitoring foundation in stable patients. Cardiac MRI was valued for initial diagnosis — particularly for amyloid evaluation and RV morphology assessment — but described as practically unusable for serial monitoring given 3-to-4-month wait times, low repeat patient compliance, and variable radiologist expertise across the region's institutions.

References

1. Humbert M, Kovacs G, Hoeper MM, et al; ESC/ERS Scientific Document Group. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618–3731. doi:10.1093/eurheartj/ehac237

2. Chin KM, Coghlan G, Grünig E, et al; 7th World Symposium on Pulmonary Hypertension. Treatment algorithm for pulmonary arterial hypertension. Eur Respir J. 2024;64(4):2401325. doi:10.1183/13993003.01325-2024

3. Kopeć G, Kurzyna M, Torbicki A, et al. Emerging therapies and new directions in the treatment of pulmonary arterial hypertension. Kardiol Pol. 2025;83(1):15–28. doi:10.33963/v.kp.102048

4. Hoeper MM, Badesch DB, Ghofrani HA, et al; STELLAR Trial Investigators. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med. 2023;388(16):1478–1490. doi:10.1056/NEJMoa2213558

5. Humbert M, McLaughlin VV, Badesch DB, et al; ZENITH Trial Investigators. Sotatercept in patients with pulmonary arterial hypertension at high risk for death. N Engl J Med. 2025;392(20):1987–2000. doi:10.1056/NEJMoa2415160