| Drug / class | Typical real-world use in HPAH/PAH | Mechanism / pathway | Key trial / program explicitly mentioned | Evidence-backed outcomes / implementation notes | Regulatory / practice note | Suggested MAXO term(s) | Source URL / year |
|---|---|---|---|---|---|---|---|
| Endothelin receptor antagonists (ERAs; bosentan, ambrisentan, macitentan) | Core background therapy; used in initial dual combination with PDE5 inhibitor for low/intermediate-risk PAH; part of initial triple therapy for high-risk patients | Blocks endothelin pathway to reduce vasoconstriction and remodeling | **AMBITION** (initial dual combination); **TRITON** (initial oral triple) | AMBITION introduced initial ERA+PDE5i dual combination in 2015; TRITON evaluated ERA+PDE5i+selexipag and “was not found superior to initial dual combination therapy” (pqac-00000020) | ESC/ERS 2022 guidance summarized in retrieved text: initial combination recommended for low/intermediate risk; ERA is part of high-risk triple therapy with s.c./i.v. prostacyclin analogue + PDE5i (pqac-00000020) | MAXO: endothelin receptor antagonist therapy; vasodilator therapy | https://doi.org/10.1183/13993003.01324-2024 (2024); dissertation excerpt citing guideline/trial summaries (pqac-00000020) |
| Phosphodiesterase-5 inhibitors (PDE5i; sildenafil, tadalafil) | Core background therapy; used in initial dual combination with ERA; part of high-risk triple therapy | Enhances nitric oxide–cGMP signaling by preventing cGMP degradation | **AMBITION**; **TRITON** | Sildenafil available for PAH since 2005; tadalafil since 2009; dual ERA+PDE5i is recommended initial combination for low/intermediate-risk patients in summarized guideline text (pqac-00000020) | Standard pathway-directed therapy predating sotatercept; part of conventional “three classical pathways” approach (pqac-00000015, pqac-00000020) | MAXO: phosphodiesterase inhibitor therapy; nitric oxide pathway agonist/vasodilator therapy | https://doi.org/10.1042/BST20231547 (2024); dissertation excerpt citing guideline/trial summaries (pqac-00000020) |
| Soluble guanylate cyclase stimulator (riociguat) | Alternative nitric oxide pathway therapy in PAH | Stimulates sGC to increase cGMP signaling | No specific trial named in retrieved evidence | Listed among current nitric oxide-pathway treatments since 2013 in retrieved treatment summary (pqac-00000020) | Included among approved PAH therapies developed over past decades; no HPAH-specific differential use retrieved | MAXO: soluble guanylate cyclase stimulator therapy; vasodilator therapy | dissertation excerpt citing treatment summary (pqac-00000020) |
| Prostacyclin analogues (epoprostenol, iloprost, treprostinil) | Background or escalation therapy; **high-risk** patients: initial triple therapy with s.c./i.v. prostacyclin analogue + ERA + PDE5i | Replaces or augments prostacyclin pathway signaling to promote vasodilation and antiproliferative effects | No specific prostacyclin trial named in retrieved evidence | Epoprostenol was first PAH-specific therapy (approved 1995); iloprost inhaled; treprostinil s.c./i.v./oral; high-risk patients are recommended initial triple therapy including s.c./i.v. prostacyclin analogue (pqac-00000020) | Established standard-of-care class before activin-pathway therapy; used across PAH including HPAH by risk-based algorithms (pqac-00000020) | MAXO: prostacyclin therapy; vasodilator therapy | dissertation excerpt citing treatment summary (pqac-00000020) |
| Prostacyclin receptor agonist (selexipag) | Escalation option and component of oral triple-combination strategies; add-on if low-risk status not achieved at follow-up in some patients | Activates prostacyclin IP receptor | **TRITON** | TRITON evaluated initial oral triple therapy including selexipag but did **not** show superiority over initial dual therapy in retrieved summary (pqac-00000020) | Part of prostacyclin pathway armamentarium; follow-up escalation may add prostacyclin receptor agonist in intermediate-low risk patients per summarized guideline text (pqac-00000020) | MAXO: prostacyclin receptor agonist therapy; prostacyclin therapy | dissertation excerpt citing treatment summary (pqac-00000020) |
| High-dose calcium channel blockers (amlodipine, felodipine, diltiazem, nifedipine) in acute vasoreactivity responders | Restricted to IPAH/HPAH/familial PAH or drug-induced PAH patients with positive vasoreactivity testing | Vasodilator therapy via calcium channel blockade | No specific trial named in retrieved evidence | Roughly **10%** of PAH patients are acute responders; responder definition in retrieved text: fall in mPAP by **≥10 mmHg** to **≤40 mmHg** with increased or unchanged cardiac output; only few are long-term responders (pqac-00000020) | Used selectively, not broadly across all HPAH; “long-term responders to CCBs” retained as subgroup in classification review (pqac-00000019, pqac-00000020) | MAXO: calcium channel blocker therapy; vasodilator therapy | https://doi.org/10.1183/13993003.01324-2024 (2024); dissertation excerpt citing treatment summary (pqac-00000020) |
| Sotatercept / activin-signaling inhibitor | Add-on / escalation therapy on background PAH treatment; proposed “fourth pathway” therapy for patients not at low risk at follow-up | ActRIIA-Fc ligand trap that reduces excess activin/GDF ligand signaling, rebalancing pro-proliferative Smad2/3 vs antiproliferative BMPR2-Smad1/5/8 signaling | **PULSAR**, **STELLAR** | In retrieved evidence, PULSAR and STELLAR showed **reduced PVR** and **increased 6MWD** when added to background therapy (pqac-00000020); review notes sotatercept was recently FDA approved for PAH but target cells/mechanism remain incompletely understood (pqac-00000015) | FDA approval **Q1 2024** and EMA approval **Q3 2024** stated in retrieved source; 2024 7th WSPH recommended activin-signaling inhibitors as an alternative escalation for PAH with intermediate-low or greater risk at follow-up (pqac-00000020) | MAXO: activin signaling inhibitor therapy; targeted molecular therapy | https://doi.org/10.1042/BST20231547 (2024); dissertation excerpt summarizing PULSAR/STELLAR and approvals (pqac-00000020); NCT04576988 STELLAR trial record (pqac-00000014) |
| Risk-based combination therapy strategy | Real-world implementation across PAH subtypes including HPAH, with therapy intensified by risk status | Uses combinations across endothelin, nitric oxide, prostacyclin, and now activin/TGF-β-related pathways | **AMBITION**, **TRITON**, **PULSAR**, **STELLAR** | Retrieved sources support: initial dual therapy for low/intermediate risk; high-risk initial triple therapy with ERA+PDE5i+s.c./i.v. prostacyclin analogue; escalation with prostacyclin receptor agonist or parenteral prostacyclin, and now activin-signaling inhibition as alternative escalation (pqac-00000020) | Reflects current practice evolution from vasodilator-only paradigms toward disease-modifying pathway targeting; conventional therapies improve exercise capacity and delay worsening but are not curative (pqac-00000015, pqac-00000020) | MAXO: combination pharmacotherapy; risk-stratified treatment escalation | https://doi.org/10.1042/BST20231547 (2024); https://doi.org/10.1183/13993003.01324-2024 (2024); dissertation excerpt (pqac-00000020) |


*Table: This table summarizes evidence-backed PAH treatments relevant to heritable pulmonary arterial hypertension, including standard pathway-directed therapies, risk-based combination strategies, and newer activin-pathway targeting with sotatercept. It is useful for linking drug classes to mechanisms, real-world use, named trials, and ontology-style MAXO treatment annotations.*