PAH in Community Practice: Algorithms and Access

Upfront Combination Therapy: Individualization, Aging Patients, and the Opsynvi Access Battle

Pulmonary arterial hypertension (PAH) management has undergone a fundamental shift from sequential monotherapy toward aggressive upfront combination therapy, codified in the 2022 ESC/ERS guidelines endorsing an ERA plus PDE5 inhibitor as standard initial treatment for non-high-risk patients and immediate triple therapy — including IV or subcutaneous prostacyclin — for those presenting at high risk.¹ The 2024 approval of macitentan/tadalafil (Opsynvi; J&J) simplified that dual backbone to a single once-daily tablet, reducing the pill burden of an already complex regimen for a population often managing multiple comorbidities.²

Furthermore, the arrival of sotatercept (Winrevair; Merck) as the first activin signaling inhibitor introduced a 4th mechanistic pathway and reshaped escalation thinking across the disease spectrum: the STELLAR trial, published in the New England Journal of Medicine in 2023, demonstrated an 84% reduction in clinical worsening events in patients on background dual or triple therapy,³ and the ZENITH trial, published in 2025, showed a 76% reduction in the composite of all-cause death, lung transplant, and PAH-related hospitalization in high-risk patients on maximal background therapy — stopped early for efficacy.⁴ Despite these advances, community practice implementation reflects a clinical reality shaped by insurance formularies, access constraints, and the absence of the staffing infrastructure that enables academic centers to execute complex PAH protocols with full coordinator support.

Against this backdrop, HCPLive convened a panel of pulmonologists, critical care physicians, and advanced practice providers from the Jacksonville, Florida region for an in-depth dinner discussion on the evolving PAH treatment landscape. The forum was moderated by Danny Pulido, MD, a pulmonary critical care specialist in private practice in Jacksonville, and included APP panelists, community pulmonologists, and colleagues from the University of Florida and Mayo Clinic Jacksonville, exploring how the same PAH treatment algorithm is executed, navigated, or constrained across different institutional contexts within a single metropolitan area.

The panel’s opening discussion surfaced an immediate point of nuance: while upfront dual combination therapy is the recognized standard, the specific sequence, timing, and agents used are shaped heavily by patient profile and institutional formulary. Pulido described starting an ERA and PDE5 inhibitor in close succession — approximately 1 week apart — to enable side effect attribution before adding a prostacyclin as a 3rd agent within 1 to 2 months. A recurring theme was the aging demographic of community PAH practices: in a retirement-heavy market like Jacksonville, patients in their 70s and 80s with labile blood pressure, renal insufficiency, and multiple comorbidities do not always tolerate the aggressive upfront approach that evidence supports in younger patients.

The group described a pragmatic middle ground — PDE5 monotherapy as a starting point for the most fragile elderly patients, with close clinical monitoring before adding an ERA. Macitentan/tadalafil’s once-daily fixed-dose combination was viewed as theoretically ideal, with patients on it consistently reporting preference. However, accessing it was described as the forum’s most visceral frustration. Insurance denials were described as near-universal on first submission, with payers accepting clinical justifications only in narrow circumstances — cognitive impairment, aspiration risk — while rejecting the routine adherence rationale that clinicians consider most valid. The AI-generated denial problem drew particular frustration: the group described payers issuing automated denials that are pharmacologically incorrect — including 1 denial of a PDE5 inhibitor because the patient was female and lacked erectile dysfunction — and noted the emerging clinical response: AI-generated rebuttal letters fighting AI-generated denials. As Pulido summarized the administrative burden: “It’s not for the weary, that’s for sure.”

What were clinicians’ real world experiences?

The sotatercept discussion produced the forum’s most clinically animated exchange. One panelist described the group’s 1st patient — a man on maximal triple therapy, clearly progressing, reluctant to transfer to an academic center — who “turned the corner” after sotatercept was added as a 4th agent. Another described echocardiographic normalization after sotatercept addition in a patient with a baseline TAPSE of 1.3, with 6-month repeat imaging showing normalized TAPSE of 2.1, normal PA pressures, normalized right ventricle, and reduced tricuspid regurgitation. The group’s consensus was that sotatercept is currently positioned as a 4th-line agent in community practice but that comfort with it is growing toward 3rd-line use, with panelists noting its particular utility in patients who cannot tolerate oral prostacyclins — as a replacement rather than addition — producing functional improvements and echocardiographic changes that exceed what those patients achieved on prostacyclin alone.

On prostacyclin transitions from IV or subcutaneous to oral or inhaled therapy, a panelist described performing these transitions in hospital under close hemodynamic monitoring, using calculated equivalency tables, acknowledging that “there’s no perfect dose transition.” Several panelists noted inhaled epoprostenol as a preferred community prostacyclin option given its up-titration flexibility and ease of use compared with oral treprostinil’s reconstitution complexity — a significant concern in elderly patients with cognitive limitations.

As 1 panelist noted of the Orenitram reconstitution problem: “I waited very long for1 patient because I [thought]there’s no way he’s going to be able to reconstitute this, and he couldn’t. I tried to get them to bring into an infusion center, but they wouldn’t. So, they brought in his daughter… that’s how we give him his medication.” The forum also identified a meaningful systemic gap that extends beyond any single drug: the absence in community practice of the 24/7 coordinator infrastructure, specialty pharmacy relationships, and ICU-based titration capacity that academic centers use to initiate and manage advanced prostacyclin therapy. Pulido described the institutional appetite for building that support as unresolved, and the group endorsed the reality that some therapeutic options — however evidence-supported — are simply not executable without the infrastructure to match.

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. Opsynvi (macitentan and tadalafil) [prescribing information]. Raritan, NJ: Janssen Pharmaceuticals; 2024.

3. 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

4. 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