📋 Key Information Summary
- Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure (mPAP) ≥20 mmHg at rest measured by right heart catheterisation (RHC) — echocardiography alone is insufficient for diagnosis.
- The WHO classification divides PH into five groups: Group 1 — Pulmonary arterial hypertension (PAH); Group 2 — Left heart disease; Group 3 — Lung disease/hypoxia; Group 4 — Chronic thromboembolic PH (CTEPH); Group 5 — Unclear/multifactorial mechanisms.
- Group 1 PAH has the most complex pharmacotherapy pathway and requires specialist management at a PH centre; all other groups focus primarily on treating the underlying cause.
- Vasoreactivity testing with inhaled nitric oxide (iNO) or IV adenosine is mandatory in Group 1 PAH — only vasoreactive responders should receive calcium channel blocker (CCB) therapy (long-term high-dose).
- Risk stratification using ESC/ERS guidelines determines treatment strategy: low risk → monotherapy or combination; intermediate risk → initial combination; high risk → initial triple combination or parenteral prostacyclin.
- Key PH biomarkers include BNP/NT-proBNP, troponin, uric acid, and cardiac MRI parameters; 6-minute walk test (6MWT) and WHO functional class (I–IV) are essential clinical measures.
- CTEPH is the only potentially curable form of PH — all patients with CTEPH should be assessed for pulmonary endarterectomy (PEA) at an experienced centre; balloon pulmonary angioplasty (BPA) is for inoperable disease.
- Riociguat (Adempas®) is PBS-listed for inoperable/recurrent CTEPH; Bosentan (Tracleer®), sildenafil (Revatio®), ambrisentan (Volibris®), and treprostinil are PBS-listed for PAH under Authority Required arrangements.
- Pregnancy in PAH carries maternal mortality of 30–50% — pregnancy is strongly contraindicated; ERA-class drugs are teratogenic and require reliable contraception.
- Aboriginal and Torres Strait Islander Australians have higher rates of rheumatic heart disease–related PH and later presentations; culturally safe screening and access to specialist services require specific strategies.
- Referral to a specialist PH centre (e.g., Royal Melbourne, Royal Prince Alfred, St Vincent's Sydney, Prince Charles Brisbane) is recommended for all confirmed PAH and CTEPH cases.
Introduction & Australian Epidemiology
Pulmonary hypertension (PH) encompasses a heterogeneous group of conditions characterised by elevated pulmonary arterial pressure leading to right ventricular failure and death if untreated. The haemodynamic definition requires a mean pulmonary arterial pressure (mPAP) ≥20 mmHg at rest measured by right heart catheterisation (RHC), updated from the prior 25 mmHg threshold at the 6th World Symposium on Pulmonary Hypertension (2018).
In Australia, pulmonary arterial hypertension (PAH, WHO Group 1) has an estimated prevalence of approximately 15–50 per million population. Idiopathic PAH (IPAH) remains the most common subtype, with female predominance (2–4:1 F:M ratio). Associated forms include connective tissue disease–associated PAH (particularly systemic sclerosis), congenital heart disease–related PAH, and portopulmonary hypertension.
The Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Thoracic Society of Australia and New Zealand (TSANZ) recommend referral to designated PH centres for all suspected PAH and CTEPH cases. Major PH centres in Australia include the Royal Melbourne Hospital PH Service, Royal Prince Alfred Hospital (Sydney), St Vincent's Hospital (Sydney), The Prince Charles Hospital (Brisbane), and Royal Adelaide Hospital.
Diagnostic delay: The median time from symptom onset to PAH diagnosis in Australia is 2–3 years. Dyspnoea on exertion is the most common presenting symptom, often initially misattributed to deconditioning, asthma, or anxiety. Early recognition and referral improves outcomes significantly.
The most common form of PH overall is Group 2 (left heart disease–related PH), which complicates up to 60–70% of patients with heart failure with preserved ejection fraction (HFpEF) and a significant proportion of those with heart failure with reduced ejection fraction (HFrEF). Group 3 (lung disease–related PH) is increasingly recognised in COPD and interstitial lung disease (ILD), particularly idiopathic pulmonary fibrosis (IPF).
CTEPH (Group 4) occurs in approximately 2–4% of patients following acute pulmonary embolism and is potentially curable with pulmonary endarterectomy. Balloon pulmonary angioplasty (BPA) has emerged as an option for inoperable CTEPH, now performed at several Australian centres.
Classification & Diagnosis
WHO Haemodynamic Classification
The 6th World Symposium on Pulmonary Hypertension (Nice 2018) refined the haemodynamic definitions. PH is classified based on RHC findings into:
| Haemodynamic Definition | Mean PAP | PCWP | PVR |
|---|---|---|---|
| Pre-capillary PH (Groups 1, 3, 4, 5) | ≥20 mmHg | ≤15 mmHg | >3 WU |
| Post-capillary PH (Group 2) | ≥20 mmHg | >15 mmHg | ≤3 WU |
| Combined pre- and post-capillary PH | ≥20 mmHg | >15 mmHg | >3 WU |
PAP = pulmonary arterial pressure; PCWP = pulmonary capillary wedge pressure; PVR = pulmonary vascular resistance; WU = Wood units
WHO Clinical Classification (Groups 1–5)
The clinical classification system groups PH by shared pathophysiology, histopathology, and management approach:
| Group | Category | Examples |
|---|---|---|
| Group 1 | Pulmonary arterial hypertension (PAH) | Idiopathic (IPAH), heritable (BMPR2), drug/toxin-induced (anorexigens, methamphetamine), associated with CTD, HIV, portal hypertension, CHD, schistosomiasis |
| Group 1′ | Pulmonary veno-occlusive disease (PVOD) / Pulmonary capillary haemangiomatosis (PCH) | Rare; often heritable (EIF2AK4 mutations); poorly responsive to PAH-specific therapy |
| Group 1″ | Persistent PH of the newborn | Failure of postnatal pulmonary vascular remodelling |
| Group 2 | PH due to left heart disease | HFrEF, HFpEF, valvular disease (mitral/aortic), congenital/acquired left heart inflow/outflow tract obstruction |
| Group 3 | PH due to lung disease and/or hypoxia | COPD, ILD/IPF, combined pulmonary fibrosis and emphysema (CPFE), OHS, OSA, developmental lung disorders |
| Group 4 | PH due to pulmonary artery obstructions | Chronic thromboembolic pulmonary hypertension (CTEPH), other pulmonary artery obstructions (angiosarcoma, arteritis) |
| Group 5 | PH with unclear and/or multifactorial mechanisms | Haematological (chronic haemolytic anaemia, myeloproliferative), systemic (sarcoidosis, LCH, NF1), metabolic (Gaucher, glycogen storage), chronic renal failure on dialysis |
Diagnostic Algorithm
The diagnostic workup follows a stepwise approach beginning with clinical suspicion based on symptoms (progressive dyspnoea, exertional syncope, chest pain, fatigue) and risk factors:
1
Clinical Suspicion
Progressive exertional dyspnoea unexplained by other causes; syncope; signs of right heart failure; risk factors (CTD, CHD, HIV, portal hypertension, anorexigens)
2
Echocardiography
First-line screening tool — estimates systolic PAP via TR jet velocity; assesses RV size/function, RA size, pericardial effusion, IVC collapsibility; grades likelihood of PH
3
Exclude Common Causes
PFTs (obstructive/restrictive), CT chest (lung disease, ILD), CT pulmonary angiography (CTEPH), echocardiography (left heart disease), V/Q scan (CTEPH screening)
4
Right Heart Catheterisation
Gold standard for diagnosis — confirms mPAP ≥20 mmHg, determines pre- vs post-capillary, measures PVR, cardiac output, SvO₂; essential before PAH-specific therapy
5
Vasoreactivity Testing
During RHC: iNO (typically 40 ppm) or IV adenosine; positive = mPAP drop ≥10 mmHg to ≤40 mmHg with maintained or increased CO — mandates CCB trial in Group 1 PAH
Echocardiographic Screening — Probability of PH
The ESC/ERS echocardiographic probability assessment integrates multiple parameters:
| Probability | Peak TR Velocity (m/s) | Additional Echo Criteria |
|---|---|---|
| Low | ≤2.8 m/s or not measurable | No other PH signs |
| Intermediate | 2.9–3.4 m/s | Presence of ≥1 additional PH sign (RV dilation, RA enlargement, septal flattening, RVOT acceleration time <105 ms, elevated IVC) |
| High | >3.4 m/s | Regardless of additional signs |
V/Q scan is the preferred screening test for CTEPH: A normal V/Q scan effectively excludes CTEPH with >97% sensitivity. CT pulmonary angiography (CTPA) has lower sensitivity for CTEPH compared with V/Q and should not be used as the sole exclusionary test. MBS item 61408 applies for V/Q scanning.
Right Heart Catheterisation
RHC is mandatory before initiating PAH-specific therapy and provides critical haemodynamic data:
- Measured parameters: mPAP, systolic/diastolic PAP, PCWP (or left ventricular end-diastolic pressure), cardiac output (thermodilution or Fick), right atrial pressure (RAP), mixed venous oxygen saturation (SvO₂)
- Calculated parameters: PVR = (mPAP − PCWP) / CO; cardiac index (CI = CO/BSA); transpulmonary gradient (TPG = mPAP − PCWP); diastolic pressure gradient (DPG = dPAP − PCWP)
- Complications: Serious adverse events occur in <1% of procedures at experienced centres; include cardiac arrhythmia, vascular injury, pneumothorax, pulmonary artery rupture (rare)
- Frequency of follow-up RHC: Typically 3–6 months after initiating therapy, then annually or as clinically indicated to guide treatment decisions
Group 1 PAH — Management
General Measures & Supportive Therapy
- Supervised exercise/rehabilitation: Improves exercise capacity, functional class, and quality of life; should be offered at PH centres under specialist supervision
- Diuretics: Loop diuretics (furosemide, bumetanide) for fluid overload and right heart failure; spironolactone commonly added
- Anticoagulation: Controversial in IPAH; consider in IPAH and anorexigen-associated PAH (warfarin, target INR 1.5–2.5); NOT recommended in CTD-PAH or CHD-PAH
- Long-term oxygen therapy: If hypoxaemic (PaO₂ <60 mmHg at rest or on exertion)
- Pregnancy avoidance: ERA-class drugs are teratogenic; reliable contraception mandatory; pregnancy carries 30–50% maternal mortality in PAH
Vasoreactivity Testing & Calcium Channel Blockers
Vasoreactivity testing is performed during RHC in all suspected Group 1 PAH patients. A positive response is defined as a reduction in mPAP ≥10 mmHg to a value ≤40 mmHg with maintained or increased cardiac output.
Critical safety point: Calcium channel blockers (CCBs) should ONLY be prescribed to vasoreactivity-positive responders. Empirical CCB therapy in non-responsive PAH may cause haemodynamic collapse and death due to loss of compensatory vasoconstriction in the systemic circulation. Only approximately 5–10% of IPAH patients are vasoreactive.
Nifedipine (vasoreactive PAH)
Adalat® · Generic · Dihydropyridine CCB
Adult dose
Start 30 mg PO daily (long-acting), titrate to 60–120 mg PO daily in divided doses; target high-dose regimen
Paediatric dose
0.5–1 mg/kg/day PO in 2–3 divided doses; titrate cautiously
Renal adjustment
None required
PBS status
✔ PBS General Benefit
Diltiazem (vasoreactive PAH)
Dilzem SR® · Generic · Non-dihydropyridine CCB
Adult dose
Start 120–180 mg PO daily (SR), titrate to 360–720 mg/day in divided doses
Paediatric dose
1.5–3 mg/kg/day PO in 3 divided doses (immediate release); limited data
Renal adjustment
Use with caution; no specific dose adjustment
PBS status
✔ PBS General Benefit
PAH-Specific Pharmacotherapy Pathways
PAH-specific therapy targets three pathogenic pathways: the endothelin pathway (ERAs), the nitric oxide–cGMP pathway (PDE5 inhibitors, sGC stimulators), and the prostacyclin pathway (prostacyclin analogues, IP receptor agonists). Current ESC/ERS guidelines recommend risk-stratified initial combination therapy.
Endothelin Receptor Antagonists (ERAs)
Bosentan
Tracleer® · Generic · Dual ETA/ETB receptor antagonist
Adult dose
62.5 mg PO BD for 4 weeks, then 125 mg PO BD maintenance
Paediatric dose
2 mg/kg PO BD (children >2 years, ≥10 kg); dose as per specialist guidance
Key monitoring
Monthly LFTs — significant hepatotoxicity risk; contraindicated if ALT/AST >3× ULN
Renal adjustment
Caution in severe renal impairment (CrCl <30 mL/min); no specific dose change
Hepatic adjustment
Contraindicated in moderate–severe hepatic impairment (Child-Pugh B/C)
PBS status
✔ PBS Authority Required — PAH (WHO Group 1), confirmed by RHC, managed by specialist
Ambrisentan
Volibris® · Selective ETA receptor antagonist
Adult dose
5 mg PO daily, may increase to 10 mg PO daily
Paediatric dose
Not established for PAH in paediatric population
Key monitoring
Monthly LFTs initially; lower hepatotoxicity risk than bosentan but still required
Renal adjustment
No dose adjustment; caution in severe renal impairment
PBS status
✔ PBS Authority Required — PAH (WHO Group 1), specialist-initiated
Macitentan
Opsumit® · Dual ETA/ETB receptor antagonist (tissue-targeting)
Adult dose
10 mg PO daily
Key advantage
Improved tissue penetration; lower hepatotoxicity risk; no mandatory monthly LFTs (periodic monitoring recommended)
Renal adjustment
No dose adjustment required
PBS status
✔ PBS Authority Required — PAH, specialist-initiated
PDE5 Inhibitors / sGC Stimulators (Nitric Oxide Pathway)
Sildenafil
Revatio® · PDE5 inhibitor
Adult dose
20 mg PO TDS (PAH dose); titrated from 20 mg BD — note: Revatio® 20 mg TDS, NOT the higher ED dosages of Viagra®
Paediatric dose
0.5–1 mg/kg PO TDS (max 20 mg TDS); weight-based dosing recommended in infants
Renal adjustment
No adjustment; caution in severe impairment
Hepatic adjustment
Reduce dose in severe hepatic impairment (Child-Pugh C)
PBS status
✔ PBS Authority Required — PAH, specialist-initiated
Tadalafil
Adcirca® · PDE5 inhibitor (once daily)
Adult dose
20 mg PO daily (up to 40 mg PO daily); once-daily dosing advantage
Paediatric dose
Not established for PAH in children
Renal adjustment
Start 20 mg daily if CrCl 30–50 mL/min; avoid if CrCl <30 mL/min or on dialysis
PBS status
✔ PBS Authority Required — PAH, specialist-initiated
Riociguat
Adempas® · Soluble guanylate cyclase (sGC) stimulator
Adult dose (CTEPH)
1 mg PO TDS initially; titrate by 0.5 mg TDS every 2 weeks; target 2.5 mg TDS
Adult dose (PAH)
1 mg PO TDS initially; titrate by 0.5 mg TDS every 2 weeks; target 2.5 mg TDS
Key warning
Contraindicated with PDE5 inhibitors (risk of severe hypotension); pregnancy contraindicated
Renal adjustment
Contraindicated in severe renal impairment (CrCl <15 mL/min); caution if on dialysis
PBS status
✔ PBS Authority Required — inoperable/recurrent CTEPH and PAH
Prostacyclin Pathway Agents
Epoprostenol (IV)
Flolan® · Veletri® · Prostacyclin analogue (IV continuous infusion)
Adult dose
Start 1–2 ng/kg/min IV continuous infusion; titrate by 1–2 ng/kg/min every 15 min acutely, then by 1–2 ng/kg/min weekly; typical maintenance 20–40 ng/kg/min
Route
Continuous IV via central venous catheter (Hickman line); requires compounding pharmacy; cold-chain for Flolan® (Veletri® is room temperature stable)
Key risks
Catheter-related infections, sepsis, line thrombosis; rebound PH on abrupt discontinuation — never abruptly stop
PBS status
✔ PBS Authority Required — PAH, specialist-initiated
Treprostinil
Remodulin® (SC/IV) · Tyvaso® (inhaled) · Orenitram® (oral) · Prostacyclin analogue
SC infusion dose
Start 1.25 ng/kg/min SC continuous infusion; titrate by 1.25 ng/kg/min weekly as tolerated; typical range 20–80 ng/kg/min
Inhaled dose
3 breaths (18 µg) per session QID via eFlow nebuliser; titrate up to 9 breaths QID
Key advantage
SC route avoids central line; lower infection risk than IV epoprostenol; inhaled formulation for combination therapy
PBS status
✔ PBS Authority Required
Selexipag
Uptravi® · Oral selective IP receptor agonist
Adult dose
200 µg PO BD initially; titrate by 200 µg BD weekly; target maintenance 400–1600 µg BD (maximum 1600 µg BD)
Key advantage
Oral prostacyclin pathway agent; avoids parenteral administration; GRIPHON trial showed reduction in morbidity/mortality
Key side effects
Headache (very common, dose-limiting), diarrhoea, nausea, jaw pain, flushing, myalgia
Renal adjustment
No dose adjustment; caution in severe renal impairment
PBS status
✔ PBS Authority Required — PAH, specialist-initiated
Combination Therapy Strategy (ESC/ERS 2022)
1
Low Risk (initial)
Initial dual combination therapy — ERA + PDE5i/sGC stimulator; reassess at 3–6 months; add prostacyclin if goals not met
2
Intermediate Risk (initial)
Initial dual combination therapy — ERA + PDE5i; escalate to triple therapy (add prostacyclin pathway agent) if risk remains intermediate or high
3
High Risk (initial)
Initial triple combination therapy — ERA + PDE5i + IV epoprostenol/SC treprostinil; parenteral prostacyclin strongly recommended as first-line component in high-risk PAH
4
Treatment Failure
If goals not met despite optimised combination therapy → referral for lung transplantation assessment (bilateral lung transplant preferred)
Riociguat + PDE5 inhibitor contraindication: Do not combine riociguat with sildenafil or tadalafil — this causes clinically significant hypotension. If switching from PDE5i to riociguat, discontinue PDE5i at least 24 hours (sildenafil) or 48 hours (tadalafil) before starting riociguat.
Risk Stratification
Risk stratification is central to PAH management and determines treatment strategy, escalation timing, and transplant referral. The ESC/ERS guidelines employ a multi-parameter approach assessing 1-year mortality risk as low (<5%), intermediate (5–10%), or high (>10%).
ESC/ERS Risk Assessment Table
| Parameter | Low Risk (<5%) | Intermediate (5–10%) | High Risk (>10%) |
|---|---|---|---|
| WHO Functional Class | I, II | III | IV |
| 6MWT (metres) | >440 m | 165–440 m | <165 m |
| Cardiopulmonary exercise testing (peak VO₂) | >15 mL/min/kg | 11–15 mL/min/kg | <11 mL/min/kg |
| BNP / NT-proBNP | BNP <50; NT-proBNP <300 ng/L | BNP 50–300; NT-proBNP 300–1400 ng/L | BNP >300; NT-proBNP >1400 ng/L |
| Echocardiographic signs | No RA dilation, no pericardial effusion | RA moderate dilation, minimal effusion | Significant RA dilation, moderate–large pericardial effusion |
| Right atrial pressure (RHC) | <8 mmHg | 8–14 mmHg | >14 mmHg |
| Cardiac index (RHC) | ≥2.5 L/min/m² | 2.0–2.4 L/min/m² | <2.0 L/min/m² |
| SvO₂ (RHC) | >65% | 60–65% | <60% |
REVEAL Risk Score
The REVEAL (Registry to Evaluate Early and Long-term PAH Disease Management) score is a validated US-derived composite scoring system incorporating 12–13 variables to estimate 1-year survival. It has been incorporated into the 2022 ESC/ERS guidelines as a complementary tool:
| REVEAL Variable | Points |
|---|---|
| Male >60 years | +2 |
| PAH aetiology — scleroderma, portal, congenital (associated higher risk) | Varies (0–4) |
| Family history of PAH or BMPR2+ | +2 |
| NYHA/WHO FC IV | +3 |
| 6MWT <165 m | +2 |
| BNP >180 pg/mL or NT-proBNP >1500 pg/mL | +2 |
| Mean RAP >14 mmHg | +1 |
| PVR >32 WU | +1 |
| DLCO <40% predicted | +1 |
| Pericardial effusion on echo | +1 |
Low risk: REVEAL score ≤6 (≥95% 1-year survival); Intermediate: 7–8 (90–95%); High risk: ≥9 (<90% 1-year survival). The online calculator is available at revealcalc.hexacath.com.
Biomarkers in PH
| Biomarker | Significance | Available in Australia |
|---|---|---|
| BNP | RV wall stress; prognostic; serial monitoring guides treatment; most widely used PH biomarker | Yes — MBS item 66808; widely available |
| NT-proBNP | Similar prognostic utility to BNP; longer half-life; influenced by renal function | Yes — MBS item 66809 |
| High-sensitivity troponin | RV micro-injury; elevated in decompensated PAH; adverse prognostic marker | Yes — MBS item 66818 |
| Uric acid | Indirect marker of tissue hypoxia and impaired cardiac output; limited specificity | Yes — widely available |
| Cardiac MRI parameters | RVEF, RV volumes, late gadolinium enhancement (LGE); most accurate for RV function assessment; emerging prognostic value | Yes — MBS items for cardiac MRI; requires specialist referral |
6-Minute Walk Test (6MWT)
- Standardised submaximal exercise test — distance, SpO₂, heart rate, Borg dyspnoea score, and blood pressure recorded
- Normal distance: approximately 400–700 m (age and sex dependent); a distance <440 m correlates with intermediate risk; <165 m with high risk
- Serial 6MWT used to track treatment response — a decline of >30–50 m is clinically significant
- SpO₂ desaturation >10% or nadir <85% during 6MWT is an adverse prognostic sign
- Performed at baseline, 3–6 months after treatment initiation, then every 3–6 months in stable patients
Treatment Goals & Targets
Goal: Achieve and maintain low-risk status. Treatment targets include: WHO FC I or II, 6MWT >440 m, BNP <50 pg/mL (or NT-proBNP <300 ng/L), normal or near-normal cardiac index (>2.5 L/min/m²), RAP <8 mmHg, SvO₂ >65%. If targets are not met within 3–6 months, treatment escalation is indicated.
Group 2–5 Management
Unlike Group 1 PAH, the primary therapeutic strategy for Groups 2–5 PH is identification and treatment of the underlying disease. PAH-specific therapies (ERAs, PDE5 inhibitors, prostacyclins) are generally NOT indicated in Group 2–3 PH and may cause harm. Exceptions exist in advanced cases referred to PH centres.
Group 2 — PH Due to Left Heart Disease
Group 2 is the most common cause of PH globally. The haemodynamic hallmark is post-capillary PH (PCWP >15 mmHg), which may be isolated (IpcPH) or combined with a pre-capillary component (CpcPH, PVR >3 WU). CpcPH carries worse prognosis.
Do NOT use PAH-specific therapies for Group 2 PH. The SERAPHIN, COMPASS-2, and MELODY trials demonstrated that bosentan and sildenafil did not improve outcomes in left heart disease–related PH and may worsen fluid retention and clinical status. Riociguat is contraindicated. Parenteral prostanoids are also contraindicated.
| Underlying Condition | Management Strategy |
|---|---|
| HFrEF | GDMT for heart failure (ACEi/ARB/ARNI, beta-blocker, MRA, SGLT2i); device therapy (ICD/CRT); LVAD/transplant if advanced; treat iron deficiency (IV ferric carboxymaltose) |
| HFpEF | SGLT2i (dapagliflozin, empagliflozin — PBS-listed); diuretics for congestion; treat AF, hypertension, obesity, OSA; spironolactone; exercise training |
| Valvular disease | Timely surgical or percutaneous intervention (mitral clip, TAVI); management of mitral regurgitation, aortic stenosis; prosthetic valve assessment |
| Constrictive pericarditis | Pericardiectomy; echocardiography and CT/MRI assessment; specialist referral |
| Left-to-right shunts (ASD, VSD, PDA) | Defect closure if Qp:Qs >1.5 and PVR <5 WU; Eisenmenger syndrome — PAH-specific therapy may be considered at specialist PH/CHD centre |
Group 3 — PH Due to Lung Disease and/or Hypoxia
PH complicating lung disease is classified as mild (mPAP 21–24 mmHg), moderate (25–34 mmHg), or severe (≥35 mmHg). Severe PH in Group 3 is termed "severe PH-ILD" or "severe PH-COPD" and may be considered for referral to a PH centre.
| Underlying Condition | Management Strategy |
|---|---|
| COPD | GOLD guideline–directed therapy; LTOT if PaO₂ ≤55 mmHg; optimise inhaler therapy; pulmonary rehabilitation; smoking cessation (varenicline, NRT — PBS-listed) |
| ILD / IPF | Antifibrotic therapy (nintedanib, pirfenidone); LTOT; consider transplant assessment; PH in IPF — poor prognosis; inhaled treprostinil studied in PH-ILD (INCREASE trial) |
| CPFE | Combined emphysema + fibrosis; disproportionate PH; LTOT; transplant referral; high risk of lung cancer |
| Obesity hypoventilation syndrome (OHS) | NIV/CPAP; weight management (GLP-1 receptor agonists if eligible); treat OSA |
| OSA | CPAP — PH typically mild and improves with CPAP compliance; reassess PH 3–6 months after CPAP initiation |
Severe PH-ILD (Group 3): For patients with mPAP ≥35 mmHg in the context of ILD, referral to a PH centre is recommended. Inhaled treprostinil (INCREASE trial) showed improved 6MWT in PH-ILD but is not yet PBS-listed for this indication in Australia. Combination lung-liver or lung-heart transplant may be considered in select cases.
Group 5 — Unclear / Multifactorial Mechanisms
Group 5 PH encompasses conditions with incompletely understood pathophysiology or multifactorial mechanisms. Management focuses on treating the underlying condition:
| Subgroup | Management |
|---|---|
| Haematological (chronic haemolytic anaemia, thalassaemia, SCD, myeloproliferative) | Optimise disease-specific therapy; exchange transfusion in SCD; hydroxyurea; specialist haematology input; PH-specific therapy may be considered in refractory cases |
| Systemic disorders (sarcoidosis, LCH, NF1, vasculitis) | Immunosuppressive therapy for active sarcoidosis; PH-specific therapy in refractory cases at PH centre; corticosteroids, methotrexate, azathioprine |
| Metabolic (Gaucher, glycogen storage diseases, thyroid disease) | Enzyme replacement for Gaucher; treat thyroid dysfunction; manage glycogen storage disease with specialist metabolic team |
| Chronic kidney disease / dialysis | Optimise dialysis; manage fluid overload; treat AV fistula–related high-output state; renal transplant if eligible |
CTEPH Management (Group 4)
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by organised thrombus in the pulmonary arteries leading to increased PVR and PH. It is the only potentially curable form of PH. CTEPH develops in approximately 2–4% of patients within 2 years following acute pulmonary embolism, though up to 40% of CTEPH patients have no documented prior PE.
Screening for CTEPH: All patients with persistent dyspnoea >3 months following acute PE should be screened for CTEPH. A V/Q scan is the preferred screening test (sensitivity >97%); a normal V/Q scan effectively excludes CTEPH. Echocardiography at 3–6 months post-PE may detect persistent PH.
CTEPH Diagnostic Criteria
- mPAP ≥25 mmHg at rest by RHC (note: this higher threshold than general PH is maintained for CTEPH to require haemodynamic significance)
- PCWP ≤15 mmHg (pre-capillary pattern)
- Evidence of chronic thromboembolic disease on imaging (CTPA, pulmonary angiography, or MRA) — ring-like stenosis, webs, bands, complete vascular occlusions
- Adequate anticoagulation for ≥3 months
Pulmonary Endarterectomy (PEA)
PEA is the treatment of choice for operable CTEPH and offers potential cure by restoring pulmonary vascular patency. Operability assessment requires multidisciplinary team discussion (MDT) involving thoracic/cardiac surgeons, PH physicians, and radiologists.
1
Referral to PEA Centre
All CTEPH patients should be assessed at a PEA centre. In Australia, experienced centres include Royal Prince Alfred Hospital (Sydney) and Royal Melbourne Hospital. International referral to Papworth Hospital (UK) or UC San Diego may be considered.
2
MDT Operability Assessment
Considers: proximal vs distal disease location, PVR, comorbidities, patient fitness for cardiopulmonary bypass; proximal disease with accessible thrombus is ideal for PEA
3
PEA Surgery
Performed under deep hypothermic circulatory arrest (DHCA); median sternotomy; requires experienced surgical team; operative mortality 2–4% at expert centres
4
Post-operative Follow-up
RHC at 3–12 months; lifelong anticoagulation (warfarin preferred, target INR 2.0–3.0); reassess for residual PH; rehabilitation
Balloon Pulmonary Angioplasty (BPA)
BPA is an interventional radiology procedure for patients with inoperable CTEPH or residual/recurrent PH after PEA. It involves staged dilation of segmental and subsegmental pulmonary arteries using balloon catheters under fluoroscopic guidance.
- Indication: Inoperable CTEPH (distal disease, significant comorbidities, patient refusal of surgery, or residual PH post-PEA)
- Procedure: Performed in 4–8 sessions at 4–6-week intervals; each session targets 1–3 segments
- Outcomes: Improved mPAP, PVR, 6MWT, and WHO FC; 5-year survival >90% in experienced centres; CTEPH centres in Australia performing BPA include Royal Prince Alfred and The Prince Charles Hospital
- Complications: Reperfusion pulmonary oedema (10–15%), pulmonary artery injury/perforation (1–2%), haemoptysis
Medical Therapy for Inoperable CTEPH
For patients with inoperable CTEPH or persistent/recurrent PH after PEA/BPA, targeted medical therapy is indicated:
Riociguat
Adempas® · sGC stimulator — CTEPH-specific indication
Adult dose
1 mg PO TDS initially; titrate by 0.5 mg TDS every 2 weeks; target 2.5 mg TDS (max 2.5 mg TDS)
Evidence
CHEST-1 trial — improved 6MWT (mean +46 m), PVR, WHO FC, NT-proBNP; CHEST-2 open-label extension showed sustained benefit at 2 years
Key contraindication
Concomitant PDE5 inhibitor use; smoking (affects drug levels)
Renal adjustment
Contraindicated if CrCl <15 mL/min
PBS status
✔ PBS Authority Required — inoperable/recurrent CTEPH, specialist-initiated
Additional agents that may be used off-label or in combination at specialist PH centres include bosentan (BENEFIT trial showed some benefit in CTEPH), macitentan, sildenafil, and treprostinil. All require specialist oversight.
Lifelong Anticoagulation
All CTEPH patients require lifelong anticoagulation to prevent recurrent thromboembolism:
- Warfarin (target INR 2.0–3.0) — traditionally preferred; required for patients on riociguat due to limited DOAC data in CTEPH
- DOACs: Edoxaban, rivaroxaban used increasingly; limited CTEPH-specific data but extrapolated from PE treatment; discuss with PH specialist
- Inferior vena cava (IVC) filter: Consider in patients with recurrent VTE despite anticoagulation or absolute contraindication to anticoagulation
CTEPH treatment algorithm: Operable CTEPH → PEA (curative intent). Inoperable CTEPH → BPA (if accessible disease) ± riociguat. Inoperable + unsuitable for BPA → riociguat ± other PAH-specific therapy. Combination of PEA + BPA + medical therapy may be required in some patients.
Special Populations
Pregnancy
Maternal mortality 30–50% in PAH — pregnancy is strongly contraindicated
All women of childbearing age with PAH require contraception counselling before starting therapy
ERA-class drugs (bosentan, ambrisentan, macitentan) are teratogenic — category X
Bosentan reduces efficacy of hormonal contraceptives — dual contraception required
PDE5 inhibitors — limited pregnancy data; teratogenic in animal studies
Sildenafil used in some pregnancy-related PH (pre-eclampsia) under specialist supervision only
Epoprostenol — safest parenteral option if pregnancy occurs despite counselling
Continued through delivery under PH specialist and obstetric anaesthesia teams; multidisciplinary care essential
Delivery planning — vaginal delivery with assisted second stage preferred; avoid general anaesthesia if possible; prostaglandin E1 (misoprostol) is a pulmonary vasodilator
High-risk obstetric unit; post-partum monitoring 72+ hours (risk of decompensation peak 1–2 weeks postpartum)
Paediatrics
PAH in children — predominantly associated with CHD (Eisenmenger syndrome), IPAH, and developmental lung disease
Referral to a paediatric PH centre (e.g., Royal Children's Hospital Melbourne, Children's Hospital Westmead)
Sildenafil — PBS authority for paediatric PAH; weight-based dosing 0.5–1 mg/kg TDS
FDA warning against chronic high-dose sildenafil in children (STARTS trial excess mortality); low-dose (PAH dosing) appears safe
Bosentan — used in children >2 years, ≥10 kg; dose 2 mg/kg BD
Monthly LFTs required; FUTURE-4 trial confirmed safety in paediatric PAH
IV epoprostenol — first-line for high-risk paediatric IPAH; bridge to transplant
Central line management is challenging in small children; infection risk higher than adults
Elderly
Group 2 PH (left heart disease) is the most common cause in the elderly
Differentiate from PAH — PAH-specific therapies are harmful in Group 2 PH
Polypharmacy considerations — drug interactions with CCBs, anticoagulants, diuretics
Bosentan has significant cytochrome P450 interactions; riociguat is affected by antacid timing
Frailty and sarcopenia affect 6MWT interpretation — consider cardiopulmonary exercise testing
Comprehensive geriatric assessment before PAH-specific therapy; consider quality-of-life outcomes
Transplant eligibility is often limited by age (>65–70 years at most centres)
Focus on medical optimisation, palliative care integration, symptom management
Renal Impairment
Bosentan — metabolised hepatically; caution in severe renal impairment; no dose adjustment but monitor closely
NT-proBNP levels are affected by GFR — interpret with caution in CKD
Riociguat — contraindicated if CrCl <15 mL/min; caution if on dialysis
Limited dialysis clearance data; specialist monitoring required
Diuretic management — aggressive diuresis for right heart failure; monitor renal function closely
Avoid nephrotoxic agents where possible; contrast use for RHC/CTPA — ensure hydration protocol
Haemodialysis-related PH (Group 5) — optimise dialysis prescription; manage AV fistula high-output state
Consider ligation/reduction of fistula if high-output PH confirmed
Hepatic Impairment
Bosentan — contraindicated in Child-Pugh B and C; hepatotoxicity risk requires monthly LFTs
Elevated baseline LFTs (>3× ULN) — do not initiate bosentan
Ambrisentan — lower hepatotoxicity risk than bosentan; use with caution in hepatic impairment
Preferred ERA in mild hepatic impairment; still requires LFT monitoring
Sildenafil — reduce dose in severe hepatic impairment (Child-Pugh C)
Portopulmonary PH — MELD exception points available for transplant listing in some jurisdictions
Portopulmonary PH — haemodynamic assessment required before liver transplant; mPAP must be <35 mmHg for transplant candidacy
PAH-specific therapy may improve haemodynamics to allow transplant eligibility
Immunocompromised
HIV-associated PAH — treat HIV with ART to achieve viral suppression; PAH-specific therapy as per Group 1
Drug interactions between ERAs/protease inhibitors — bosentan contraindicated with certain PIs; macitentan safer
CTD-associated PAH (immunosuppressed context) — manage underlying CTD with rheumatologist
SSc-PAH has poorest prognosis among PAH subtypes; consider early combination therapy and transplant assessment
Immunosuppressed patients with CTEPH — anticoagulation risk–benefit; consider DOACs over warfarin for easier management
Monitor for opportunistic infections with prostacyclin central line use
Aboriginal and Torres Strait Islander Health Considerations
Aboriginal and Torres Strait Islander Health
Aboriginal and Torres Strait Islander Australians experience a disproportionate burden of conditions leading to pulmonary hypertension, yet face significant barriers to timely diagnosis, specialist access, and treatment. Rheumatic heart disease (RHD), a preventable condition virtually eliminated in non-Indigenous Australia, remains a leading cause of Group 2 PH in remote Aboriginal and Torres Strait Islander communities, particularly in the Northern Territory, Far North Queensland, and Western Australia.
Key Epidemiological Disparities
- Rheumatic heart disease (RHD): Aboriginal and Torres Strait Islander Australians have among the highest RHD rates globally (incidence up to 150/100,000 in NT children); RHD leads to significant valvular disease and subsequent Group 2 PH
- Chronic lung disease: Higher rates of COPD, bronchiectasis, and post-infectious lung disease contributing to Group 3 PH; smoking prevalence remains high (approximately 40% in Aboriginal and Torres Strait Islander adults vs 11% non-Indigenous)
- Later presentation: Aboriginal and Torres Strait Islander patients with PH present at more advanced stages due to healthcare access barriers and delayed referral pathways
- Congenital heart disease: Higher prevalence of undiagnosed congenital heart disease contributing to PAH in remote communities
RHD and PH in Aboriginal and Torres Strait Islander Australians: Significant mitral or aortic valve disease from RHD is a preventable cause of Group 2 PH. Timely cardiac surgery for severe valvular disease can prevent or reverse PH. The Australian Government Rheumatic Fever Strategy funds RHD control programs in endemic regions. All clinicians caring for Aboriginal and Torres Strait Islander patients in high-prevalence areas should consider RHD in the differential diagnosis of unexplained dyspnoea and refer for echocardiography.
📚 References
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