Pulmonary Hypertension

📋 Key Information Summary

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Pulmonary hypertension (PH) is defined as mean pulmonary arterial pressure (mPAP) >20 mmHg at rest, measured by right heart catheterisation (RHC); pulmonary vascular resistance (PVR) ≥3 WU further characterises pre-capillary disease.
The WHO Classification divides PH into five groups: Group 1 (PAH), Group 2 (LHD), Group 3 (lung disease), Group 4 (CTEPH), Group 5 (multifactorial); correct classification is critical as therapies are group-specific.
Group 1 PAH-specific therapies (e.g., Epoprostenol, Sildenafil, Bosentan, Selexipag) are NOT indicated for Groups 2–5 PH and may cause harm if used inappropriately.
Transthoracic echocardiography (TTE) is the first-line screening tool; RHC is the gold standard for definitive haemodynamic assessment and vasoreactivity testing.
V/Q scan is mandatory to exclude chronic thromboembolic pulmonary hypertension (CTEPH — Group 4) in all patients with unexplained PH.
PAH risk stratification uses REVEAL 2.0 or ESC/ERS criteria (low/intermediate/high risk) to guide initial combination therapy decisions.
Initial dual combination therapy (ERA + PDE5i) is now standard for newly diagnosed PAH; triple therapy is recommended for high-risk patients.
Epoprostenol (Flolan®, Veletri®) remains first-line for severe/acute vasodilator-responsive PAH; requires continuous IV infusion via central venous access.
Sildenafil (Revatio®) is PBS-listed (Authority Required) for PAH; Bosentan (Tracleer®) requires PBS Authority approval with hepatology monitoring.
Pulmonary endarterectomy (PEA) is the treatment of choice for CTEPH (Group 4); balloon pulmonary angioplasty (BPA) is an emerging option for inoperable disease.
Lung transplantation referral should be discussed early; Australian centres include St Vincent's Hospital Sydney, The Alfred Melbourne, and Prince Charles Hospital Brisbane.
PH in Aboriginal and Torres Strait Islander peoples is associated with higher prevalence of rheumatic heart disease and chronic lung disease; access to specialist PH centres requires proactive coordination from remote and rural communities.
All PAH-specific therapies are teratogenic; reliable contraception is mandatory for women of childbearing potential (pregnancy category D — Sildenafil; X — Bosentan, Ambrisentan).
Serial 6-minute walk distance (6MWD), NT-proBNP, and echocardiographic parameters guide treatment response monitoring every 3–6 months.
Anticoagulation is recommended for Group 1 PAH (controversial) and mandatory for Group 4 CTEPH with warfarin (target INR 2.0–3.0); DOACs are not recommended for CTEPH.

Introduction & Australian Epidemiology

Pulmonary hypertension (PH) is a haemodynamic condition defined as mean pulmonary arterial pressure (mPAP) >20 mmHg at rest, measured by right heart catheterisation (RHC). Pulmonary arterial hypertension (PAH, Group 1) specifically requires the additional criterion of pulmonary vascular resistance (PVR) ≥3 Wood Units (WU) with a pulmonary arterial wedge pressure (PAWP) ≤15 mmHg.

In Australia, the estimated prevalence of PAH is approximately 15–50 per million population, with an annual incidence of 1–2 per million. Idiopathic PAH (iPAH) is the most common Group 1 subtype, predominantly affecting women aged 30–50 years. Connective tissue disease–associated PAH (CTD-PAH), particularly in systemic sclerosis, accounts for a significant proportion of incident PAH diagnoses.

Group 2 PH (due to left heart disease) is by far the most common cause of PH in Australia, reflecting the high burden of heart failure (~500,000 Australians). Group 3 PH is prevalent in the context of Australia's significant chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) burden, including dust-related lung diseases. Group 4 CTEPH (chronic thromboembolic pulmonary hypertension) has an estimated prevalence of 5–40 per million, with the diagnosis often delayed due to non-specific symptoms.

Without treatment, Group 1 PAH carries a poor prognosis — median survival historically 2.8 years from diagnosis in iPAH. With modern PAH-specific therapies, survival has improved significantly, with reported 5-year survival rates exceeding 60–70% in contemporary registries. Early diagnosis, correct WHO group classification, and appropriate evidence-based therapy are essential to optimise outcomes.

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Classification is critical: PAH-specific therapies (e.g., Epoprostenol, Sildenafil, Bosentan, Selexipag) have demonstrated efficacy ONLY in WHO Group 1 (PAH) and Group 4 (CTEPH — partially). They are NOT indicated and may cause clinical deterioration if used in Groups 2 and 3. Correct group assignment by RHC and multidisciplinary team review is mandatory before initiating therapy.

WHO Classification of Pulmonary Hypertension (Groups 1–5)

The current Nice (6th World Symposium, 2018) WHO classification organises pulmonary hypertension into five clinical groups based on aetiology and pathophysiology. This classification guides investigation, treatment selection, and clinical trial participation.

WHO Group	Name	Key Subtypes & Examples	Haemodynamic Profile	Therapy Approach
Group 1	Pulmonary Arterial Hypertension (PAH)	1.1 Idiopathic (iPAH); 1.2 Heritable (BMPR2, ACVRL1, ENG mutations); 1.3 Drug- and toxin-induced (e.g., fenfluramine, dasatinib); 1.4 Associated with CTD (scleroderma, SLE, MCTD); 1.5 HIV infection; 1.6 Portal hypertension (portopulmonary); 1.7 Congenital heart disease (Eisenmenger); 1.8 Schistosomiasis	mPAP >20 mmHg, PVR ≥3 WU, PAWP ≤15 mmHg	PAH-specific therapies: ERAs, PDE5is, sGC stimulators, prostacyclin analogues
Group 1′	Pulmonary Veno-occlusive Disease (PVOD) / Pulmonary Capillary Haemangiomatosis	Often heritable (EIF2AK4 biallelic mutations); rare; can mimic iPAH	Pre- and post-capillary features; low DLCO	PAH drugs used with caution (risk of pulmonary oedema); transplant evaluation early
Group 2	PH Due to Left Heart Disease	2.1 Heart failure with reduced EF (HFrEF); 2.2 Heart failure with preserved EF (HFpEF); 2.3 Valvular heart disease (mitral/aortic); 2.4 Congenital/acquired inflow/outflow obstruction	PAWP >15 mmHg (isolated post-capillary, IpcPH); ± PVR elevation (combined pre- and post-capillary, CpcPH)	Treat underlying LHD: diuretics, ACEi/ARB, device therapy; NO PAH-specific drugs
Group 3	PH Due to Lung Disease & Hypoxia	3.1 COPD; 3.2 ILD (IPF, CTD-ILD); 3.3 OHS; 3.4 Developmental lung disorders	Usually post-capillary component; disproportionate PH may warrant PAH Rx discussion	Oxygen therapy, optimise lung disease; PAH drugs not recommended routinely; refer for LTOT if PaO₂ <55 mmHg
Group 4	Chronic Thromboembolic PH (CTEPH)	Organised thrombus with fibrotic remodelling of pulmonary vasculature post-PE	mPAP >20 mmHg, PVR ≥3 WU, organised fibrotic obstruction on CTPA/RHC	Pulmonary endarterectomy (PEA) — curative; BPA for inoperable; Riociguat (Adempas®) PBS-listed
Group 5	PH with Unclear &/or Multifactorial Mechanisms	Haematological (chronic haemolytic anaemia, myeloproliferative); metabolic (GSD, thyroid); systemic (sarcoidosis, Histiocytosis X); others (tumour embolism, CKD/dialysis)	Variable; depends on underlying condition	Treat underlying cause; PAH therapy individualised in specialised centres

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Common misclassification pitfall: Patients with diastolic dysfunction (HFpEF) and breathlessness may be incorrectly diagnosed as PAH. RHC with PAWP measurement is essential. Inappropriate PAH therapy in Group 2 PH can cause pulmonary oedema and haemodynamic collapse.

Pathophysiology & Haemodynamics

Normal Pulmonary Haemodynamics

The pulmonary circulation is normally a low-pressure, low-resistance system. Normal values: mPAP 14 ± 3 mmHg, PAWP 6–12 mmHg, PVR 0.3–2.0 WU, cardiac output 5–6 L/min. In PH, chronic elevation of pulmonary arterial pressures leads to right ventricular (RV) pressure overload, RV dilatation, tricuspid regurgitation, and ultimately right heart failure.

Vascular Remodelling in Group 1 PAH

PAH is characterised by a proliferative and anti-apoptotic vascular remodelling process involving all three layers of the pulmonary arterial wall:

Intimal: Eccentric and concentric intimal fibrosis; plexiform lesions (characteristic of iPAH)
Medial: Hypertrophy and hyperplasia of vascular smooth muscle cells (VSMCs)
Adventitial: Fibrosis and inflammatory cell infiltration
In-situ thrombosis: Microthrombosis in small pulmonary arteries

Key Pathobiological Pathways

Three major molecular pathways are dysregulated in PAH and serve as therapeutic targets:

Pathway 1

Prostacyclin Deficiency

Reduced prostacyclin synthase → decreased PGI₂ → loss of vasodilation and anti-proliferation. Targeted by Epoprostenol (IV), Treprostinil (SC/IV/Inhaled/Oral), Iloprost (inhaled), Selexipag (oral).

Target: IP receptor → ↑ cAMP

Pathway 2

Endothelin-1 Overproduction

↑ ET-1 → vasoconstriction, fibrosis, proliferation via ET_A and ET_B receptors. Targeted by Bosentan (dual), Ambrisentan (selective ET_A), Macitentan (dual, tissue-penetrating).

Target: ET_A/ET_B receptors

Pathway 3

NO–sGC–cGMP Pathway Dysregulation

Reduced NO bioavailability → ↓ cGMP → vasoconstriction, remodelling. Targeted by Sildenafil (PDE5i, ↑cGMP), Tadalafil (PDE5i), Riociguat (sGC stimulator, directly ↑cGMP).

Target: sGC / PDE5

Haemodynamic Definitions (RHC-Based)

Parameter	Definition / Threshold	Significance
Pulmonary Hypertension	mPAP >20 mmHg	Mandatory diagnostic criterion (revised 6th WSPH 2018)
Pre-capillary PH (PAH, CTEPH)	mPAP >20 mmHg, PAWP ≤15 mmHg, PVR ≥3 WU	Defines Group 1 (PAH) and Group 4 (CTEPH)
Isolated post-capillary PH (IpcPH)	mPAP >20 mmHg, PAWP >15 mmHg, PVR <3 WU	Typical of Group 2 (LHD)
Combined pre- and post-capillary PH (CpcPH)	mPAP >20 mmHg, PAWP >15 mmHg, PVR ≥3 WU	Group 2 with significant pulmonary vascular disease; PAH Rx may be discussed at PH MDT
Acute vasoreactivity testing (AVT)	IV Epoprostenol or Inhaled Nitric Oxide → ≥10 mmHg fall in mPAP to mPAP ≤40 mmHg, with ↑ or unchanged CO	Positive test → trial of high-dose CCB therapy (limited to ~5% of iPAH)

Right Ventricular Adaptation and Failure

The RV is a thin-walled, compliant chamber adapted to low-pressure output. In PH, chronic pressure overload causes RV hypertrophy initially (adaptive), followed by dilatation, reduced contractility, and tricuspid regurgitation (maladaptive). RV failure is the most common cause of death in PAH. Biomarkers of RV strain (NT-proBNP, troponin), echocardiographic indices (TAPSE, RV S′, RVFAC, RVGLS), and cardiac MRI-derived RV volumes guide prognosis.

Investigations

Investigation of suspected pulmonary hypertension follows a structured approach: (1) confirm PH on echocardiography, (2) classify by WHO group, (3) assess severity and prognosis. All investigations should be performed at or coordinated through a specialist PH centre.

Essential & Recommended Investigations

ESSENTIAL Transthoracic Echocardiography (TTE) First-line screening. Estimates RVSP via TR jet velocity + RAP. Assesses RV size, function (TAPSE, RVFAC), LV, valvular disease, pericardial effusion. Probability categorisation (ESC 2022): unlikely (TRV <2.8 m/s), possible (2.8–3.4), high (>3.4). MBS item 55105.

ESSENTIAL Right Heart Catheterisation (RHC) Gold standard for haemodynamic diagnosis. Mandatory before PAH-specific therapy. Measures: RA, RV, PA, PAWP pressures; CO (thermodilution/Fick); PVR; acute vasoreactivity testing (AVT). Specialist centres only. Not individually MBS-itemised; bundled under cardiac catheterisation (55132).

ESSENTIAL V/Q Scan (Ventilation-Perfusion Scintigraphy) Mandatory to exclude CTEPH (Group 4) in all PH patients. Sensitivity >96% for CTEPH; a normal V/Q scan effectively excludes CTEPH. MBS item 61347 (lung perfusion scan). CTPA follows if V/Q mismatch identified.

AVAILABLE CT Pulmonary Angiography (CTPA) Complements V/Q scan. Characterises CTEPH morphology (webs, bands, stenoses, complete obstruction). Identifies lung parenchymal disease. MBS item 56808.

AVAILABLE CT Chest (HRCT) Assessment of interstitial lung disease (ILD), emphysema. Key for Group 3 PH classification. MBS item 56808.

AVAILABLE Pulmonary Function Tests (PFTs) Spirometry, DLCO, lung volumes. DLCO <45% predicted in scleroderma-PAH is a red flag; very low DLCO may suggest PVOD. MBS item 11505.

AVAILABLE 6-Minute Walk Test (6MWT) Functional capacity assessment; distance, Borg dyspnoea score, SpO₂. Used in REVEAL risk score and as a treatment response endpoint. MBS item 11506.

AVAILABLE NT-proBNP / BNP Biomarker of RV strain. Used in risk stratification (REVEAL 2.0, ESC/ERS). Serial monitoring guides treatment response. MBS item 66825.

SPECIALIST Cardiac MRI Gold standard for RV volume and function assessment. Detects pericardial effusion, myocardial fibrosis. Prognostic: RV ejection fraction, LGE. Limited availability — tertiary centres.

SPECIALIST Autoimmune Serology (ANA, ENA, dsDNA, ACA, anti-Scl-70) Screen for CTD-PAH. All iPAH patients should be screened. Scleroderma patients require annual screening echo + PFTs. Refer to rheumatology if positive.

AVAILABLE HIV Serology, Hepatitis Serology, Liver Function Exclude Group 1 associated causes. Portal hypertension screening if hepatic disease detected.

SPECIALIST Genetic Testing (BMPR2, ACVRL1, ENG, EIF2AK4) Heritable PAH screening. Offered through specialised genetics services. BMPR2 mutations in ~75% of familial PAH. Genetic counselling pre- and post-test. EIF2AK4 testing for suspected PVOD.

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Australian PH Centres: Specialist PH diagnostic workup and RHC should be performed at designated PH centres — Royal Adelaide Hospital, St Vincent's Hospital Sydney, The Alfred Melbourne, Prince Charles Hospital Brisbane, Royal Perth Hospital, Fiona Stanley Hospital Perth. Referral guidelines: any unexplained dyspnoea with RVSP >40 mmHg or TRV >3.0 m/s.

Risk Stratification & Severity Scoring

Risk stratification in Group 1 PAH determines treatment goals and escalation. The ESC/ERS 2022 guidelines use a three-strata model (low, intermediate, high risk) based on WHO functional class, 6MWD, NT-proBNP, echocardiography, RHC, and the presence of pericardial effusion.

Low Risk

Estimated 1-Year Mortality <5%

WHO FC I–II; 6MWD >440 m; NT-proBNP <300 ng/L; RA area <18 cm²; no pericardial effusion; CI ≥2.5 L/min/m²; SvO₂ >65%

Goal: maintain low-risk status; review 3–6 monthly

Intermediate Risk

Estimated 1-Year Mortality 5–10%

WHO FC III; 6MWD 165–440 m; NT-proBNP 300–1100 ng/L; RA area 18–26 cm²; trace/small pericardial effusion; CI 2.0–2.4 L/min/m²; SvO₂ 60–65%

Goal: escalate therapy; consider adding third agent or parenteral prostacyclin

High Risk

Estimated 1-Year Mortality >10%

WHO FC IV; 6MWD <165 m; NT-proBNP >1100 ng/L; RA area >26 cm²; moderate/large pericardial effusion; CI <2.0 L/min/m²; SvO₂ <60%; signs of RVF

Goal: aggressive escalation; IV epoprostenol; assess transplant listing

REVEAL 2.0 Risk Calculator

The REVEAL 2.0 score is widely used in Australian PH centres. It incorporates WHO group, age, sex, renal function (eGFR), BMI, vital signs, 6MWD, NT-proBNP, WHO FC, RA pressure, PVR, pericardial effusion, and DLCO to generate a continuous risk score and category (low, average, moderately high, high, very high). It is validated for reassessment at follow-up visits.

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Treat-to-target approach: ESC/ERS 2022 recommend a treat-to-target strategy in PAH — aim for low-risk status at follow-up. If intermediate/high risk persists at 3–6 months despite dual combination therapy, escalate to triple therapy including parenteral prostacyclin, or refer for lung transplant assessment.

Management of Pulmonary Hypertension

General & Supportive Measures (All Groups)

Supervised exercise / pulmonary rehabilitation: Improves 6MWD, QoL, and WHO FC; evidence from randomised trials
Oxygen therapy: Maintain SpO₂ ≥90%; assess need with sleep oximetry; Long-Term Oxygen Therapy (LTOT) if PaO₂ <55 mmHg (PBS-subsidised home oxygen)
Diuretics: Loop diuretics (Furosemide 20–80 mg PO OD, or Bumetanide 0.5–1 mg PO OD) for RV volume overload and peripheral oedema; monitor electrolytes
Vaccination: Annual influenza, COVID-19 booster, pneumococcal (Prevenar 13 then Pneumovax 23), pertussis, RSV where eligible
Psychosocial support: PH diagnosis is associated with significant anxiety and depression; refer to psychology/support groups (Pulmonary Hypertension Association Australasia)
Avoid: High-altitude travel, pregnancy (mandatory contraception — see Special Populations), strenuous isometric exercise, decongestants (pseudoephedrine), smoking

Anticoagulation in PH

Anticoagulation recommendations vary by WHO group:

Group 1 PAH: Consider warfarin (INR 2.0–3.0) in iPAH/heritable PAH (observational data only; not RCT-proven). Generally not recommended in CTD-PAH or CHD-PAH due to bleeding risk.
Group 4 CTEPH: Lifelong anticoagulation is mandatory. Warfarin (INR 2.0–3.0) is preferred; DOACs are NOT recommended due to risk of organised thrombus progression. Riociguat is PBS-listed for inoperable CTEPH.
Groups 2, 3, 5: Anticoagulation per underlying condition indication (e.g., AF, VTE); no PH-specific benefit.

PAH-Specific Therapy — WHO Group 1 (Drug Detail)

Current Australian guidelines recommend initial dual oral combination therapy (endothelin receptor antagonist + PDE5 inhibitor or sGC stimulator) for newly diagnosed PAH, with escalation to triple therapy including parenteral prostacyclin for intermediate–high risk patients.

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Epoprostenol

Flolan® · Veletri® · Prostacyclin analogue (PGI₂)

Adult dose Initial: 2–4 ng/kg/min IV continuous infusion; titrate by 1–2 ng/kg/min every 15 min acutely, or 1–2 ng/kg/min every 1–2 weeks chronically. Typical maintenance: 20–40 ng/kg/min. Must NOT be stopped abruptly (rebound PH).

Paediatric dose 2–4 ng/kg/min IV; titrate to response. Used in severe paediatric PAH at specialist centres.

Route Continuous IV infusion via central venous catheter (tunnelled Hickman-type line); Flolan® requires cold-chain reconstitution; Veletri® is room-temperature stable

Key monitoring Haemodynamics at initiation (ICU/HDU setting); line infection risk; jaw pain, flushing, diarrhoea, thrombocytopenia; refrigeration requirement (Flolan®)

Renal adjustment None required; adjust loop diuretics as needed

PBS status 🔑 Authority Required (Specialist)

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Sildenafil

Revatio® · PDE5 inhibitor

Adult dose 20 mg PO TDS (licensed dose for PAH); some centres use 40–80 mg TDS off-label. Do NOT use 25/50/100 mg (Viagra® dosing).

Paediatric dose 0.5–1 mg/kg/dose PO TDS (max 20 mg TDS). SPRINT trial caution re higher doses in paediatric PAH.

Route Oral; suspension available for paediatric use

Key interactions Absolute contraindication with nitrates (risk of severe hypotension); caution with CYP3A4 inhibitors (ketoconazole, ritonavir — reduce dose); Riociguat contraindicated with PDE5i

Renal adjustment CrCl <30 mL/min: use with caution; max 20 mg BD

PBS status 🔑 Authority Required — PAH (WHO Group 1)

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Tadalafil

Adcirca® · PDE5 inhibitor

Adult dose 40 mg PO OD for PAH

Route Oral; once daily (convenient vs sildenafil TDS)

Key interactions Same as sildenafil — avoid nitrates; caution CYP3A4 inhibitors

PBS status 🔑 Authority Required — PAH

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Bosentan

Tracleer® · Dual endothelin receptor antagonist (ET_A + ET_B)

Adult dose 62.5 mg PO BD × 4 weeks (initiation), then 125 mg PO BD (maintenance)

Paediatric dose Weight <10 kg: 31.25 mg BD; 10–20 kg: 31.25 mg BD; 20–40 kg: 62.5 mg BD; >40 kg: adult dose. BREATHE-3 trial data.

Route Oral (tablets); dispersible tablet formulation available

Key monitoring Hepatotoxicity: LFTs monthly × 3 months, then every 3 months. Discontinue if ALT >5× ULN or symptomatic hepatitis. Also causes: teratogenicity (Category X — pregnancy contraindicated), peripheral oedema, anaemia (Hb monitoring), testicular atrophy.

Renal adjustment None required; contraindicated in severe hepatic impairment (Child-Pugh C)

PBS status 🔑 Authority Required — Specialist initiation

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Ambrisentan

Volibris® · Selective ET_A receptor antagonist

Adult dose 5 mg PO OD; increase to 10 mg OD if tolerated

Route Oral

Key notes Lower hepatotoxicity risk vs Bosentan. Peripheral oedema, nasal congestion, headache. Monthly LFTs still recommended.

PBS status 🔑 Authority Required — PAH

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Macitentan

Opsumit® · Dual ERA (tissue-penetrating)

Adult dose 10 mg PO OD

Route Oral

Key notes SERAPHIN trial: reduced morbidity/mortality vs placebo. Lower hepatotoxicity than Bosentan. Oedema, headache, nasopharyngitis.

PBS status 🔑 Authority Required — PAH

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Riociguat

Adempas® · Soluble guanylate cyclase (sGC) stimulator

Adult dose 1 mg PO TDS initially; titrate by 0.5 mg TDS every 2 weeks to max 2.5 mg TDS. Maintain BP >90/50 mmHg during titration.

Route Oral

Key notes CONTRAINDICATED with PDE5 inhibitors (sildenafil, tadalafil) — risk of severe hypotension. PATENT-1 trial: improved 6MWD and PVR in PAH. CHEST-1 trial: approved for inoperable CTEPH. Concomitant smoking reduces efficacy.

PBS status 🔑 Authority Required — PAH & CTEPH

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Selexipag

Uptravi® · Oral prostacyclin IP receptor agonist

Adult dose 200 µg PO BD initially; titrate by 200 µg BD weekly to max 1600 µg BD (or maximum tolerated dose). Take with food.

Route Oral

Key notes GRIPHON trial: reduced composite morbidity/mortality by 40%. Jaw pain (49%), diarrhoea, headache, flushing. Can be combined with ERA + PDE5i (triple oral therapy).

PBS status 🔑 Authority Required — PAH

Treatment Algorithm — WHO Group 1 PAH (ESC/ERS 2022)

1

Initial Assessment & Risk Stratification

RHC confirmation. Assess risk category (low / intermediate / high) using ESC/ERS criteria. Rule out Group 2 (LHD) and Group 3 (lung disease) — PAH-specific Rx contraindicated in these groups.

2

Acute Vasoreactivity Testing (AVT)

RHC with IV Epoprostenol or inhaled NO. If positive (≥10 mmHg drop in mPAP to ≤40 mmHg with ↑/stable CO) → trial of high-dose CCB (Amlodipine or Nifedipine). Only ~5% of iPAH are vasoreactive; reassess at 3–12 months.

3

Initial Dual Combination Therapy (All Risk Strata)

Start ERA + PDE5i (or ERA + sGC stimulator). E.g., Macitentan 10 mg OD + Sildenafil 20 mg TDS. AMBITION trial demonstrated superiority of upfront dual combination vs sequential.

4

Reassess at 3–6 Months

WHO FC, 6MWD, NT-proBNP, echo, haemodynamics. If LOW risk achieved → maintain. If INTERMEDIATE–HIGH risk persists → escalate.

5

Triple Therapy Escalation

Add oral Selexipag (or parenteral prostacyclin — Epoprostenol IV / Treprostinil SC). If HIGH risk at presentation, consider initial triple therapy including IV Epoprostenol.

6

Lung Transplantation Referral

Refer when: (a) progressive disease on triple therapy, (b) WHO FC III–IV despite maximal medical therapy, (c) declining 6MWD / rising NT-proBNP / RV failure. Donor organ availability is limited; early referral is critical.

CTEPH (Group 4) — Specific Management

1

Lifelong Anticoagulation

Warfarin INR 2.0–3.0 is standard. DOACs are not recommended (risk of organised thrombus progression — limited data). Start immediately on diagnosis.

2

Operability Assessment (PEA)

All CTEPH patients must be assessed by a PEA surgical centre (The Alfred Melbourne, St Vincent's Sydney). PEA is potentially curative. Assessment includes CTPA, RHC, pulmonary angiography, surgical team review.

3

Pulmonary Endarterectomy (PEA)

Deep hypothermic circulatory arrest. Surgical removal of organised fibrotic thrombus from pulmonary arteries. Perioperative mortality 2–5% at experienced centres. Cure in selected patients.

4

Balloon Pulmonary Angioplasty (BPA)

For inoperable or residual PH post-PEA. Requires specialist interventional radiology. Not widely available in Australia; referral to international centres may be needed. Emerging Australian programmes at select tertiary centres.

5

Medical Therapy (Inoperable CTEPH)

Riociguat (Adempas®) 1–2.5 mg TDS — PBS Authority Required. CHEST-1 trial: improved 6MWD (+46 m) and PVR. Selexipag (GRIPHON subgroup) may also be considered. Macitentan (MERIT-1) emerging data.

Special Populations

🤰 Pregnancy

General

PH in pregnancy carries maternal mortality of 17–33%. Prevention of pregnancy is the safest strategy. Long-acting reversible contraception (LARC) — IUD (Mirena®) or subdermal implant (Implanon NXT®) — is recommended.

Sildenafil

Pregnancy category D. Risk of fetal harm in animal studies. If pregnancy occurs and continuation is elected, may be used with caution under specialist supervision.

Bosentan / Ambrisentan / Macitentan

Pregnancy category X. Absolute contraindication. Teratogenic. Discontinue before conception; reliable contraception mandatory.

Epoprostenol

Category B3. Can be continued in pregnancy at experienced PH centres (not teratogenic but haemodynamic management is critical). Planned delivery at tertiary centre with ICU.

Delivery

Vaginal delivery preferred with early epidural and assisted second stage. Caesarean only for obstetric indications. Continuous invasive haemodynamic monitoring. Avoid ergometrine (pulmonary vasoconstriction).

👶 Paediatric PH

Aetiologies

PAH-CHD (Eisenmenger syndrome), BPD-related PH, idiopathic PAH, PPHN. Classification follows paediatric Nice classification. Neonatal PH (PPHN) managed with inhaled NO and optimisation of underlying cause.

Sildenafil

0.5–1 mg/kg/dose PO TDS (max 20 mg TDS). SPRINT trial concern: higher doses (4–6 mg/kg/dose) associated with increased mortality in paediatric PAH — use licensed doses only.

Bosentan

Weight-based dosing (see drug card above). Dispersible tablet formulation available. LFT monitoring as per adults.

Epoprostenol

IV continuous infusion as per adult dosing; central line placement in children requires surgical expertise. Reassess for transition to oral therapy when feasible.

Referral

All paediatric PH should be managed at specialist paediatric centres (e.g., Sydney Children's Hospital, RCH Melbourne, Queensland Children's Hospital) with paediatric PH expertise.

👴 Elderly (≥65 years)

Diagnostic challenge

Group 2 PH (HFpEF) is most common in elderly; careful RHC interpretation (PAWP) essential to avoid misclassification as PAH.

Drug tolerability

Sildenafil — hypotension risk increased; start low (20 mg OD–BD) and titrate. Bosentan — peripheral oedema can be confused with heart failure; monitor closely. Epoprostenol — line infection risk higher; consider quality of life vs burden of IV therapy.

🫘 Renal Impairment

Sildenafil

CrCl <30 mL/min: max 20 mg BD (reduced clearance). Monitor for hypotension.

Bosentan / Macitentan / Ambrisentan

No dose adjustment required; use with caution in dialysis patients. Volume shifts during haemodialysis can exacerbate hypotension.

Riociguat

No specific renal adjustment; not studied in dialysis. Titrate with extra caution.

🫁 Hepatic Impairment

Bosentan

Contraindicated in moderate–severe hepatic impairment (Child–Pugh B/C). LFT monitoring mandatory. Causes dose-dependent hepatotoxicity.

Sildenafil

AUC increased in hepatic impairment; start at 20 mg OD–BD and titrate cautiously.

Portopulmonary HT

PAH therapy can be used in portopulmonary hypertension if pre-transplant liver assessment is favourable. Non-selective beta-blockers should be discontinued (worsen PH). Liver transplant evaluation is key.

🦠 Immunocompromised / HIV

HIV-PAH

PAH can occur in HIV (prevalence ~0.5%). PAH-specific therapies are effective. Bosentan and Sildenafil interact with antiretrovirals: ritonavir inhibits CYP3A4 → ↑ sildenafil levels (reduce to 20 mg OD); efavirnez induces CYP3A4 → ↓ bosentan levels. ART optimisation is essential.

Lung Transplantation in Pulmonary Hypertension

Lung transplantation remains the definitive treatment for selected patients with PAH or CTEPH refractory to maximal medical therapy. Bilateral lung transplantation is the preferred procedure. Heart-lung transplantation is reserved for patients with severe congenital heart disease or inoperable cardiac pathology.

Referral Criteria for Transplant Assessment

WHO FC III–IV on optimised PAH-specific therapy (including triple therapy with parenteral prostacyclin)
Declining 6MWD (<330 m) or rising NT-proBNP (>1100 ng/L) despite therapy
Haemodynamic deterioration: CI <2.0 L/min/m², RA pressure >15 mmHg, mPAP >50% systemic MAP
Refractory RV failure requiring inotropic support
Recurrent syncope or severe pericardial effusion
PVOD / pulmonary capillary haemangiomatosis — early referral recommended

Australian Transplant Centres

Centre	Location	Capabilities
St Vincent's Hospital	Sydney, NSW	Bilateral lung transplant; PH programme; PEA
The Alfred Hospital	Melbourne, VIC	Bilateral lung transplant; National PEA centre; advanced PH
The Prince Charles Hospital	Brisbane, QLD	Bilateral lung transplant; PH programme

Post-Transplant Considerations

Immunosuppression: Triple therapy — Tacrolimus + Mycophenolate + Prednisolone (wean to 5 mg OD by 12 months)
Primary graft dysfunction (PGD) is the leading cause of early mortality
Chronic lung allograft dysfunction (CLAD) / obliterative bronchiolitis — main cause of late graft loss
5-year survival post-lung transplant: approximately 50–60%

Monitoring & Follow-Up

Patients with PAH require lifelong specialist follow-up with a treat-to-target approach. Reassessment at 3–6 month intervals guides treatment escalation decisions.

Assessment	Frequency	Purpose
Clinical review (WHO FC, symptoms)	Every 3–6 months	Risk stratification; treatment response
NT-proBNP	Every 3–6 months	RV strain biomarker; risk category assignment
6-Minute Walk Test	Every 3–6 months	Functional capacity; prognostic
Echocardiography	Every 6–12 months	RV size/function; TR severity; pericardial effusion
RHC (haemodynamics)	Every 12–24 months (or if clinical change)	Definitive haemodynamic assessment; treatment goals
LFTs (on Bosentan)	Monthly × 3 months, then 3-monthly	Hepatotoxicity screening
Hb (on Bosentan)	Baseline, 1 month, 3-monthly	Anaemia monitoring (Bosentan reduces Hb)
Pregnancy test (WCBA)	Monthly (on ERA/X-category drugs)	Teratogenicity prevention

✅

Treatment goals (ESC/ERS 2022): Aim to achieve and maintain low-risk status: WHO FC I–II, 6MWD >440 m, NT-proBNP <300 ng/L, RA area <18 cm², no pericardial effusion, CI ≥2.5 L/min/m². If goals are not met at 3–6 months, escalate therapy in a stepwise fashion.

Aboriginal and Torres Strait Islander Health Considerations

Aboriginal and Torres Strait Islander Health

Epidemiology

Aboriginal and Torres Strait Islander Australians experience a higher burden of conditions leading to PH, including rheumatic heart disease (RHD — Group 2 PH), chronic lung disease (Group 3 PH), and ischaemic heart disease. RHD prevalence is up to 30 times higher in Indigenous Australians, with chronic rheumatic valvular disease (especially mitral stenosis) causing significant pulmonary hypertension. Chronic suppurative lung disease and bronchiectasis are more prevalent, contributing to Group 3 PH.

Diagnostic access

Access to echocardiography and specialist PH centres is limited in remote and very remote communities. Tele-echocardiography and visiting specialist services through the Australian Government's Outreach programs can facilitate early detection. RHC requires transfer to tertiary centres, which involves significant logistical and financial barriers, particularly from remote NT, QLD, and WA communities.

RHD and PAH

RHD-related mitral stenosis is a major cause of Group 2 PH. Secondary prevention with benzathine penicillin G (BPG) 1.2 MU IM every 3–4 weeks (PBS-listed) is essential. RHD registers (e.g., NT RHD Register) facilitate adherence monitoring. Surgical valve intervention (mitral valvuloplasty/replacement) should be considered early where feasible.

Medication access & PBS

PAH-specific therapies (Sildenafil, Bosentan, Macitentan, etc.) are Authority Required under PBS, requiring specialist initiation and documentation. In remote communities, dispensing may require coordination with Remote Area Aboriginal Health Services (RAAHS) and community pharmacies. Telehealth consultations with PH specialists can facilitate Authority approval and ongoing prescription management.

Cultural safety

Diagnosis of a chronic life-limiting condition like PAH requires culturally sensitive communication. Involving Aboriginal Health Workers (AHWs) and Aboriginal Liaison Officers (ALOs) in the care team improves understanding and engagement. Yarning-based approaches to explaining complex conditions, acknowledging family and community roles in decision-making, and providing written resources in plain language (with visual aids) are recommended. Sorry Business and cultural obligations should be accommodated in appointment scheduling.

Travel & logistics

Patients from remote communities may need to travel >500 km for PH specialist review, RHC, and advanced therapies (e.g., Epoprostenol initiation). Patient-assisted travel schemes (PATS — state/territory specific) and RFDS retrieval services are critical. Continuous IV Epoprostenol requires reliable central venous access, refrigeration, and medication supply — challenging in remote settings without home nursing support.

Lung transplantation

Transplant candidacy requires pre- and post-transplant care at metropolitan centres for 6–12 months. Barriers include family separation, housing, employment, and cultural disconnection from Country. Social work and Indigenous support services at transplant centres are essential to facilitate equitable access.

Data & closing the gap

National PH registries (e.g., ANZPHTS — Australian and New Zealand Pulmonary Hypertension Transplant Society) should include Indigenous status data to monitor disparities. The AIHW regularly reports on cardiovascular disease burden in Indigenous Australians. Closing the Gap targets for cardiovascular health are relevant to RHD-related PH prevention.

📚 References

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2. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1):1801913. doi:10.1183/13993003.01913-2018
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