PAH targeted therapy

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general principles

1. Confirm Group 1 PAH — requires RHC showing mPAP > 20 mmHg, 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.

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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 trial showed 50% reduction in clinical failure with ambrisentan + tadalafil vs. either monotherapy.

high risk

• Initial therapy: Triple combination including parenteral prostacyclin (IV or SC).
• Referral: Urgent evaluation for lung transplantation.

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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) — the new standard (STELLAR 2024)

• Mechanism: Fusion protein that traps activin ligands, restoring balance between pro-proliferative and anti-proliferative signalling in the pulmonary vasculature.
• Indication: Add-on therapy for adults with PAH (WHO FC II–III) on stable background therapy.
• Dosing: 0.3 mg/kg or 0.7 mg/kg SC every 3 weeks.
• Monitoring: Haemoglobin/haematocrit (risk of erythrocytosis) and platelets (risk of thrombocytopenia).

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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., selexipag or sotatercept) or transition to parenteral prostacyclins.
• Transition: Riociguat may be more effective than sildenafil in patients not reaching goals (REPLACE trial).

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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.
• Ignore anticoagulation needs — though evidence is evolving, anticoagulation is generally not recommended for IPAH anymore unless other indications exist (Bertoletti, JACC. 2025).
• Prescribe ERAs in pregnancy — highly teratogenic; mandatory contraception.