Combination Therapy, Adherence, and Access: A PAH Expert Roundtable

When Risk Scores Miss the Picture: Echo, Heart Rate Recovery, and the Case for Serial Catheterization

The pulmonary arterial hypertension treatment algorithm has been substantially revised since the 2022 ESC/ERS guidelines, with 3 post-guideline approvals — sotatercept (Winrevair; Merck), Opsynvi (macitentan/tadalafil fixed-dose combination; J&J), and high-dose sildenafil 80 mg three times daily — and the 7th World Symposium on Pulmonary Hypertension’s 2024 treatment algorithm formally incorporating activin signaling inhibition into escalation decisions at intermediate- and high-risk follow-up visits.^1,2

Real-world implementation, however, continues to be shaped as much by non-pharmacologic factors — insurance formulary, patient social circumstances, geographic access, and dominant regional disease etiology — as by clinical trial data. A published mediation analysis using individual patient data from the AMBITION and FREEDOM-EV trials found that even the best-performing validated risk tools mediated only 19% to 29% of the treatment effect on clinical worsening outcomes, versus 19% for change in 6-minute walk distance alone, with none approaching the 50% threshold considered adequate for a surrogate endpoint — underscoring the clinical reality that risk scores, while important, remain imperfect guides to individual treatment decisions.³

The expanding evidence base for sotatercept, now approaching two years of post-approval use at high-volume centers, has simultaneously generated a set of real-world safety signals — including intrapulmonary shunting on bubble echocardiography, erythrocytosis with a newly proposed volume-depletion mechanism, and pericardial effusion patterns not prominently described in pivotal trials — that are actively reshaping clinical practice at experienced centers.⁴

Against this backdrop, HCPLive convened a panel of PAH specialists, critical care physicians, and advanced lung disease providers from Phoenix, Arizona for an in-depth roundtable on the evolving PAH treatment landscape. The forum was moderated by Akshay Muralidhar, MD a pulmonary vascular specialist at St. Joseph’s Hospital in Phoenix with expertise in cardiopulmonary exercise testing and exercise right heart catheterization, and included colleagues from Banner Health and Dignity Health, including physicians managing the Phoenix lung transplant program. The discussion was structured around 5 themes: initial drug selection and deviations from standard dual therapy, risk stratification beyond the score, sotatercept’s expanding real-world profile, prostacyclin transition strategies, and transplant referral timing.

Sotatercept’s Real-World Signal Profile and the Meth-PAH Imperative

The forum’s most substantive clinical discussion centered on monitoring and the profound gap between validated risk scores and true hemodynamic trajectory in individual patients. The panel converged on heart rate recovery after 6MWT, RV free wall longitudinal strain on echocardiography, and serial right heart catheterization as the most clinically informative monitoring parameters — with one panelist citing cases of patients walking 500 to 550 meters and scoring well on risk calculators who were found on catheterization to have PVRs of 10 to 11 Wood units, unchanged or worsened from baseline. Muralidhar shared a case of a 40-year-old woman with IPAH on dual therapy whose 6MWT dropped 100 meters over three months without her ever admitting to worsening symptoms — a pattern he described as confirming the clinical value of serial catheterization, particularly in young patients who underreport decline. One panelist has implemented annual RHC for all patients whose therapy is still being titrated as a standard protocol, describing the catheterization as the equivalent of urine drug screening in methamphetamine-associated disease: an objective data point that overcomes denial.

The discussion of sotatercept’s emerging real-world safety profile surfaced 2 notable signals not yet formally described in peer-reviewed literature: intrapulmonary shunting identified on annual bubble echocardiography — hypothesized to reflect sotatercept’s TGF-beta pathway modulation creating conditions for AVM formation, particularly in CTD-predisposed patients — and a new mechanistic hypothesis for erythrocytosis suggesting decreased circulating blood volume rather than a direct erythropoietic effect, which would reframe the hemoglobin rise as a hemodynamic phenomenon rather than a hematopoietic one.⁴

Dose reduction to 0.3 or 0.5 mg/kg was described as the standard management approach for shunting, with several centers reporting clinical benefit preservation at the lower dose. As a panelist noted of the shunting signal: “I reduced her dose. I don’t want to take her off it because otherwise she’s functionally doing very well.”

The transplant and trial design discussions surfaced equally important themes. The panel issued a clear consensus recommendation that any PAH patient on quadruple therapy should be established with a transplant center proactively — not at the point of decompensation — with a specific case cited of a patient managed collaboratively between Phoenix and Mayo Clinic for 3 years who was transferred on ECMO and transplanted within 20 days of arrival because he was already known to the program. The lung allocation score system’s well-known bias against PAH — and its persistence in the newer CAS model — was acknowledged as a systemic barrier, with exception applications based on elevated RA pressure described as a practical workaround. The panel’s discussion of trial endpoints crystallized into a clear position: the field has outgrown 6MWT as a primary endpoint, with data showing it mediates only 19% of treatment effect on clinical outcomes, and the time has come to push for time to clinical improvement as the primary threshold — a change that would require substantially larger trials but would more accurately capture the patient-meaningful benefit of modern therapy.³

Pipeline enthusiasm centered on seralutinib (Gossamer Bio) and the broader reconceptualization of PAH as an anti-proliferative target — treating the disease as a vascular cancer rather than a vasoconstrictive condition — as the most consequential research direction for the next decade.

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. Blette BS, Ventetuolo CE, Appleby DH, et al. Study of risk assessment scores as surrogate endpoints in pulmonary arterial hypertension trials. Am J Respir Crit Care Med. 2025;212(3):616–625. doi:10.1164/rccm.202411-2210OC

4. Reddy YNV, Frantz RP, Miranda WR, et al. Sotatercept in pulmonary arterial hypertension: central, hematologic, and peripheral mechanisms of benefit. J Am Coll Cardiol. Published online March 2026. doi:10.1016/j.jacc.2026.02.5103

5. Elkashef A, Rawson RA, Anderson AL, et al. Bupropion for the treatment of methamphetamine dependence. Neuropsychopharmacology. 2008;33(5):1162–1170. doi:10.1038/sj.npp.1301481