PAH targeted therapy

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general principles

1. Confirm Group 1 PAH — requires RHC showing mPAP > 20 mmHg (≥ 25 mmHg by ESC/ERS 2022 guidelines), PAWP ≤ 15 mmHg, and PVR > 2 Wood units.
2. Acute vasoreactivity testing — mandatory for IPAH, heritable PAH, and drug-induced PAH.
3. Risk stratification — use the ESC/ERS 3-strata or 4-strata model (6MWD, NT-proBNP, WHO functional class, RHC haemodynamics).
4. Upfront combination therapy — preferred for most treatment-naïve patients without significant comorbidities.
5. Specialist centre referral — particularly for high-risk patients and those requiring parenteral therapy.

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treatment pathways

1. vasoreactive patients (~5–10% of IPAH)

• Definition: Drop in mPAP by ≥ 10 mmHg to reach an absolute value of ≤ 40 mmHg with preserved/increased CO.
• Treatment: High-dose calcium channel blockers (CCB) (e.g., nifedipine, diltiazem, amlodipine).
• Prognosis: Excellent if response is maintained (Sitbon, Circulation. 2005).
• Caveat: Must reassess at 3–6 months; if not WHO FC I/II with near-normal haemodynamics → switch to PAH-targeted therapy.

2. non-vasoreactive patients

low or intermediate risk

• Initial therapy: Upfront dual oral combination (ERA + PDE5i).
• Evidence: AMBITION (2015) showed 50% reduction in clinical failure with ambrisentan + tadalafil vs. either monotherapy.
• Triple oral therapy not superior: TRITON (2024) showed initial triple oral therapy (ERA + PDE5i + selexipag) provided no benefit over dual therapy.

high risk

• Initial therapy: Triple combination including parenteral prostacyclin (IV or SC) — Class IIa recommendation (evidence limited to case series and registry data).
• Referral: Urgent evaluation for lung transplantation.
• Sotatercept: ZENITH (2025) — HR 0.24 for death, transplant, or hospitalisation ≥ 24 h in high-risk patients; stopped early for efficacy.

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drug classes & mechanisms

Pathway	Class	Agents	Key points
Nitric Oxide	PDE5 inhibitors	Sildenafil, Tadalafil	Increase cGMP; do not combine with riociguat (hypotension risk)
	sGC stimulators	Riociguat	Direct sGC stimulation; preferred in CTEPH and some PAH (REPLACE trial)
Endothelin	ERAs	Ambrisentan, Bosentan, Macitentan	Block ET-1; monitor LFTs (bosentan); check Hb (anaemia); teratogenic
Prostacyclin	Prostacyclin analogues	Epoprostenol (IV), Treprostinil (IV/SC/Inh), Iloprost	Potent vasodilators; epoprostenol is the gold standard for high-risk disease
	IP receptor agonists	Selexipag	Oral agent; reduces hospitalisation (GRIPHON)
TGF-β	Activin signalling inhibitor	Sotatercept (Winrevair)	First disease-modifying agent; improves 6MWD and PVR (STELLAR 2024)

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sotatercept (Winrevair)

• Mechanism: Fusion protein that traps activin ligands, restoring balance between pro-proliferative and anti-proliferative signalling in the pulmonary vasculature — first disease-modifying agent in PAH.
• Evidence:
  • STELLAR (2024) — HR 0.16 for death or nonfatal clinical worsening (84% risk reduction) when added to background therapy (WHO FC II–III).
  • HYPERION (2025) — HR 0.24 for clinical worsening composite (death, hospitalisation, transplant, or exercise deterioration) when added within the first year after diagnosis; NNT 5 over 12 months. Stopped early for efficacy.
  • ZENITH (2025) — HR 0.24 for major outcomes only (death, transplant, or hospitalisation ≥ 24 h) in high-risk patients. Stopped early for efficacy.
• Dosing: 0.3 mg/kg or 0.7 mg/kg SC every 3 weeks.
• Monitoring: Haemoglobin/haematocrit (erythrocytosis risk), platelets (thrombocytopenia risk), blood pressure. Watch for epistaxis and telangiectasia.

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monitoring and escalation

• Goal: Reach and maintain low-risk status.
• Follow-up: Every 3–6 months with 6MWD, NT-proBNP, and functional class assessment.
• Escalation: If patient remains at intermediate or high risk despite dual therapy, add a third agent (e.g., sotatercept or parenteral prostacyclin). Note: selexipag as add-on to dual oral therapy did not improve outcomes in TRITON (2024).
• Transition: Riociguat may be considered over sildenafil in patients not reaching goals (REPLACE 2020) — Class IIb recommendation.

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what NOT to do

• CCBs without vasoreactivity testing — dangerous and ineffective.
• Combine PDE5i and Riociguat — contraindicated due to severe hypotension.
• Delay parenteral therapy in high-risk patients — delay increases mortality.
• Blanket anticoagulation — no longer universally recommended (2022 ESC/ERS). Evidence is conflicting: some registries suggest benefit in IPAH, others show no association or potential harm in CTD-PAH (Bertoletti, JACC. 2025). Current approach: individualised case-by-case decision weighing bleeding risk vs. potential benefit.
• Prescribe ERAs in pregnancy — highly teratogenic; mandatory contraception.