PAH Combination Therapy and Escalation: Clinical Forum Perspectives

Treatment of pulmonary arterial hypertension (PAH) now spans 5 therapeutic pathways, and the options within them continue to expand. Recent developments include FDA approval of a once-daily single-tablet combination of macitentan and tadalafil, supported by the phase 3 A DUE trial, and a September 2026 European Respiratory Society (ERS) guideline update recommending add-on sotatercept for patients who remain at intermediate-low, intermediate-high, or high risk.1,2 How clinicians sequence oral, inhaled, parenteral, and injectable therapies in practice increasingly depends on risk assessment, payer requirements, and patient preference.

In September 2026, Marc Simon, MD, MS, director of pulmonary vascular disease and the Pulmonary Hypertension Comprehensive Care Center at the University of California, San Francisco (UCSF), moderated a clinical forum in San Francisco. Participants included pulmonologists, advanced heart failure and critical care cardiologists, and a nurse practitioner from UCSF, Kaiser Permanente, and California Pacific Medical Center. The discussion covered initial combination therapy, risk reassessment, escalation beyond dual therapy, and long-term monitoring.

Upfront Combination Therapy and PAH Risk Assessment

Participants described upfront dual therapy with a phosphodiesterase 5 (PDE5) inhibitor and an endothelin receptor antagonist (ERA), consistent with the 2022 European Society of Cardiology (ESC)/ERS guidelines,3 as their default for newly diagnosed patients without high-risk features. Several said they deviate from calculated risk categories when clinical concern outweighs the score, particularly in young patients with high hemodynamic burden, a group in which 1 participant said risk scores tend to underestimate risk. Heritable disease, poor right ventricular (RV) function, and a cardiac index below 2 L/min/m2 were cited as triggers for earlier escalation.

For reassessment, 1 participant said they repeat the full initial ESC risk stratification at follow-up rather than relying on abbreviated noninvasive tools, which omit imaging. Participants noted that echocardiographic RV assessment varies considerably between readers, and several said they push their echo labs to report tricuspid annular plane systolic excursion, fractional area change, and free wall strain routinely. Telemedicine was described as a barrier to obtaining 6-minute walk tests, leaving some clinicians more reliant on natriuretic peptides and functional class.

Single-Tablet Combinations, Adherence, and Access

Participants described lower pill burden and a single refill as reasons patients prefer the single-tablet combination, and 1 participant who offers patients the choice said most select it. Others noted that some patients receive their PDE5 inhibitor and ERA from separate pharmacies on mismatched refill cycles, which a single tablet avoids. Participants practicing in an integrated health system said they typically start generic ERA and PDE5 inhibitor combinations without delay.

Payer coverage was described as variable. According to 1 participant, an upfront denial delayed a patient's PAH therapy by about 2 months, and that participant now starts the components separately before transitioning. Another noted that when an ERA is added as part of a combination tablet, it can be harder to identify which component is responsible for new edema.

Escalation Beyond Dual Oral Therapy in PAH

Participants who manage patients admitted in cardiogenic shock, many with methamphetamine-associated PAH, described defaulting to triple therapy with selexipag when parenteral therapy is not pursued, and several said these patients often do well in follow-up. Selexipag was also described as the most common oral option when transitioning stable patients off infusion therapy. Participants recommended slower selexipag titration with a step back when adverse effects emerge, noting that specialty pharmacies often titrate aggressively toward the maximum dose.

Several participants said their threshold for adding sotatercept has fallen, while others said they hesitate to use it in young patients given limited long-term data. For inhaled treprostinil, participants reported titrating dry powder formulations well above starting doses, citing the absence of a ceiling effect for prostacyclins, and some described combining oral selexipag with inhaled treprostinil in patients who decline parenteral therapy.

Long-Term Safety Monitoring Across PAH Therapies

Participants emphasized agent-specific adverse event monitoring. For sotatercept, whose efficacy was established in the phase 3 STELLAR trial,4 participants reported pericardial effusions, gastrointestinal bleeding, and hypoxemia from intrapulmonary shunting, and some described monitoring hemoglobin every 3 months. For oral and inhaled prostacyclin pathway agents, participants cited gastrointestinal effects, jaw pain, myalgias, cough, and throat irritation as the main drivers of dose limitation.

"But these meds have side effects, and I think a key part of the follow-up is not just how's your breathing, how far are you walking, what's your BNP, what are your side effects, it's specific to the drug, right?" Simon said.

Participants also expressed caution about transitioning stable patients off parenteral prostacyclin, noting that US patients on infusion therapy are often those who most need it. In 1 participant's practice, therapy was successfully withdrawn in a patient with methamphetamine-associated PAH who achieved abstinence, with assessments every 3 months, though others characterized such outcomes as exceptions.

References

1. Grünig E, Jansa P, Fan F, et al. Randomized trial of macitentan/tadalafil single-tablet combination therapy for pulmonary arterial hypertension. J Am Coll Cardiol. 2024;83(4):473-484. doi:10.1016/j.jacc.2023.10.045

2. Kovacs G, Zeder K, Humbert M, et al. European Respiratory Society clinical practice guidelines update for the treatment of pulmonary arterial hypertension. Eur Respir J. Published online September 7, 2026. doi:10.1183/13993003.01178-2026

3. Humbert M, Kovacs G, Hoeper MM, et al. 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

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