Pulmonary Arterial Hypertension
Also known as: PAH, WHO Group 1 Pulmonary Hypertension
Pulmonary arterial hypertension (PAH) is a progressive disease of the small pulmonary arteries that raises pulmonary vascular resistance and leads to right heart failure.
Right heart catheterisation shows a mean pulmonary artery pressure over 20 mm Hg, a wedge pressure of 15 mm Hg or less and a pulmonary vascular resistance over 2 Wood units.
It is a group 1 pulmonary hypertension. Causes are idiopathic, heritable (BMPR2 in most, also ACVRL1, ENG, SMAD9, CAV1, KCNK3, TBX4), drug and toxin induced, and associated conditions: connective tissue disease (especially systemic sclerosis), HIV infection, portal hypertension, congenital heart disease and schistosomiasis.
Prevalence is about 50 in every million adults, with a female predominance in idiopathic disease. In sub-Saharan Africa, schistosomiasis, HIV, sickle cell disease and rheumatic heart disease are important causes of pulmonary hypertension, and left heart disease is the commonest cause overall.
Untreated idiopathic PAH has a median survival of under 3 years. With modern therapy, 5-year survival is about 60 to 70%.
Pathophysiology. Endothelial dysfunction causes vasoconstriction and proliferation of smooth muscle and endothelial cells, with intimal, medial and plexiform lesions and in situ thrombosis.
Imbalance of endothelin-1, nitric oxide and prostacyclin signalling, and loss of BMPR2 function, drive remodelling. Rising resistance overloads the right ventricle, which hypertrophies, dilates and fails.
- Exertional dyspnoea (usually the first symptom), fatigue, presyncope or syncope on exertion, chest pain, palpitations, abdominal distension, oedema and haemoptysis.
- Loud pulmonary second sound, right ventricular heave, right sided fourth sound, tricuspid regurgitation murmur, pulmonary regurgitation murmur, raised jugular venous pressure with large v waves, hepatomegaly, ascites and oedema.
- Hoarseness from compression of the left recurrent laryngeal nerve by a dilated pulmonary artery.
- Features of the cause: Raynaud phenomenon and sclerodactyly, stigmata of liver disease, clubbing and cyanosis in congenital heart disease, telangiectasia.
Red flags.
- Syncope, haemoptysis or rapid progression
- Signs of right heart failure at rest
- Functional class IV
- Right atrial pressure over 14 mm Hg or cardiac index under 2.0 L/min/m2
- Pericardial effusion or severe right ventricular dilatation
- NT-proBNP over 1,100 ng/L
- Pregnancy
- Echocardiography. Peak tricuspid regurgitation velocity over 2.8 m/s suggests pulmonary hypertension (over 3.4 m/s is high probability). Also right atrial area, right to left ventricle ratio, septal flattening, TAPSE under 17 mm, pulmonary acceleration time under 105 ms, pericardial effusion and congenital lesions.
- ECG (right axis deviation, right ventricular hypertrophy, P pulmonale) and chest X-ray.
- Exclude other groups. Pulmonary function with diffusing capacity, blood gases, high resolution CT, ventilation perfusion scan (a normal scan excludes chronic thromboembolic disease) and CT pulmonary angiography, overnight oximetry or sleep study.
- Right heart catheterisation confirms the diagnosis and gives right atrial pressure, cardiac index, wedge pressure and resistance.
- Vasoreactivity testing in idiopathic, heritable and drug induced disease: inhaled nitric oxide 10 to 20 ppm. A positive result is a fall in mean pulmonary artery pressure of 10 mm Hg or more to 40 mm Hg or less with unchanged or raised cardiac output.
- Cause. HIV, hepatitis B and C, antinuclear, anti-centromere, anti-Scl-70 and anti-RNP antibodies, schistosomal serology with stool and urine examination in endemic regions, sickle cell screen, liver ultrasound for portal hypertension, thyroid function, and genetic testing (BMPR2) with counselling.
- Function and risk. Six minute walk distance, NT-proBNP, cardiopulmonary exercise test.
| Marker | Low risk | Intermediate risk | High risk |
|---|---|---|---|
| Functional class | I to II | III | IV |
| Syncope | None | Occasional | Repeated |
| Six minute walk | Over 440 m | 165 to 440 m | Under 165 m |
| NT-proBNP | Under 300 ng/L | 300 to 1,100 ng/L | Over 1,100 ng/L |
| Right atrial pressure | Under 8 mm Hg | 8 to 14 mm Hg | Over 14 mm Hg |
| Cardiac index | 2.5 L/min/m2 or more | 2.0 to 2.4 L/min/m2 | Under 2.0 L/min/m2 |
| Mixed venous saturation | Over 65% | 60 to 65% | Under 60% |
Differential diagnosis.
- Pulmonary hypertension from left heart disease (wedge pressure over 15 mm Hg), including mitral stenosis
- Pulmonary hypertension from lung disease and hypoxia, and sleep apnoea
- Chronic thromboembolic pulmonary hypertension and acute pulmonary embolism
- Pulmonary veno occlusive disease and pulmonary capillary haemangiomatosis
- Pulmonary vein stenosis and fibrosing mediastinitis
- Sickle cell and other haematological disease
- Sarcoidosis
- Congenital heart disease with shunt
- Anaemia and asthma or other causes of dyspnoea
Manage in a pulmonary hypertension centre. Choose therapy by risk and comorbidity.
General measures.
- Pregnancy is contraindicated (maternal mortality about 20 to 30%). Use effective contraception (progestogen only methods, copper device or sterilisation), because bosentan lowers the effect of hormonal contraceptives.
- Oxygen when arterial oxygen is under 8 kPa (60 mm Hg). Supervised exercise training.
- Diuretics for congestion: furosemide 40 mg orally once daily in the morning, increased to 80 to 120 mg daily as needed (higher doses in renal impairment under specialist care), with sodium, potassium and creatinine monitoring. Spironolactone 25 mg orally once daily, increased to 50 mg once daily, with potassium and creatinine at 1 week and 4 weeks. Withhold at potassium over 5.5 mmol/L and avoid at eGFR under 30 mL/min/1.73 m2.
- Correct iron deficiency. Vaccinate against influenza, pneumococcus and COVID-19. Avoid high altitude, decongestants and dehydration.
- Warfarin to an INR of 1.5 to 2.5 is used only in selected patients with idiopathic, heritable or drug induced disease. It is avoided with systemic sclerosis and with portal hypertension and varices.
- Atrial flutter or fibrillation is poorly tolerated, so use rhythm control. Avoid non-dihydropyridine calcium channel blockers and be cautious with beta blockers.
Vasoreactive responders (about 5 to 10% of idiopathic disease): modified release nifedipine 30 mg orally once daily, increased every 1 to 2 weeks to 120 to 240 mg daily, maximum 240 mg daily, or amlodipine 5 mg once daily, increased to 20 mg (maximum 20 mg daily in this setting). Contraindicated in right heart failure and in non-responders. Reassess at 3 to 4 months, and add PAH therapy unless functional class is I to II with near normal haemodynamics.
Drug therapy for non-responders.
- Low or intermediate risk: initial combination of an endothelin receptor antagonist with a phosphodiesterase type 5 inhibitor (for example ambrisentan with tadalafil). Use monotherapy or cautious combination in older patients with cardiopulmonary comorbidity.
- High risk: initial triple therapy including a parenteral prostacyclin, under specialist care.
- Escalate when risk does not reach low risk at 3 to 6 months.
| Drug | Dose | Key points |
|---|---|---|
| Sildenafil | 20 mg orally three times daily, maximum 60 mg daily | Contraindicated with nitrates and riociguat. Headache, flushing, hypotension, visual and hearing change |
| Tadalafil | 20 mg orally once daily, increased to 40 mg once daily after 4 weeks if tolerated, maximum 40 mg daily | Start at 20 mg for creatinine clearance 31 to 80 mL/min. Avoid under 30 mL/min and in severe liver impairment. Contraindicated with nitrates and riociguat |
| Bosentan | 62.5 mg orally twice daily for 4 weeks, then 125 mg twice daily (62.5 mg twice daily under 40 kg), maximum 250 mg daily | Liver enzymes monthly and haemoglobin every 3 months. Contraindicated in pregnancy, moderate to severe liver impairment, and with ciclosporin and glibenclamide |
| Ambrisentan | 5 mg orally once daily, increased to 10 mg, maximum 10 mg daily | Oedema and anaemia. Contraindicated in pregnancy and idiopathic pulmonary fibrosis. Liver enzymes monthly where required |
| Macitentan | 10 mg orally once daily, maximum 10 mg daily | Contraindicated in pregnancy. Haemoglobin and liver enzymes at baseline and as indicated. Avoid with strong CYP3A4 inhibitors and inducers (ketoconazole, ritonavir, rifampicin) |
| Riociguat | 1 mg orally three times daily, increased by 0.5 mg every 2 weeks to 2.5 mg three times daily, maximum 7.5 mg daily | Start 0.5 mg three times daily if hypotension is a risk. Contraindicated in pregnancy and with nitrates and phosphodiesterase type 5 inhibitors. Smoking lowers levels |
| Selexipag | 200 microgram orally twice daily, increased by 200 microgram twice daily each week to the highest tolerated dose, maximum 1,600 microgram twice daily | Headache, diarrhoea, jaw pain. Avoid with strong CYP2C8 inhibitors (gemfibrozil). Start 200 microgram once daily in moderate liver impairment |
| Treprostinil | 1.25 ng/kg/min subcutaneously or intravenously, increased by 1.25 ng/kg/min weekly for 4 weeks, then by 2.5 ng/kg/min weekly to the effective dose (usually 20 to 80 ng/kg/min) | Start 0.625 ng/kg/min in liver impairment. Infusion site pain with the subcutaneous route. Never stop abruptly |
| Epoprostenol | 2 ng/kg/min intravenously by central line, increased by 2 ng/kg/min every 15 minutes or longer to the effective dose (usually 20 to 40 ng/kg/min) | Half life of minutes, so pump failure is an emergency. Line sepsis. Jaw pain and flushing |
| Sotatercept | 0.3 mg/kg subcutaneously once, then 0.7 mg/kg every 3 weeks | Add on for functional class II to III. Check haemoglobin and platelets before the first doses. Contraindicated in pregnancy. Telangiectasia and epistaxis |
- Schistosomiasis. Praziquantel 40 mg/kg orally as a single dose for active infection. It does not reverse established vascular disease.
- HIV-associated disease. Antiretroviral therapy, with careful interaction checks for protease inhibitors and bosentan, macitentan and sildenafil.
- Right heart failure in intensive care. Avoid hypotension, hypoxia and acidosis. Furosemide intravenously for congestion, dobutamine 2.5 to 5 microgram/kg/min (maximum 20 microgram/kg/min) and noradrenaline 0.05 microgram/kg/min (usual maximum 0.5 microgram/kg/min), inhaled nitric oxide or intravenous prostacyclin, and extracorporeal support as a bridge. Avoid intubation when possible.
- Refractory disease. Lung transplantation referral early (functional class III to IV on dual therapy, or intermediate to high risk). Atrial septostomy as a palliative bridge.
Special groups.
- Pregnancy: counsel against it. When pregnancy occurs, offer early termination, otherwise manage in a centre with a multidisciplinary team, with delivery planned and prostacyclin and heparin as indicated.
- Children: weight based dosing under paediatric pulmonary hypertension supervision.
- Older adults: favour monotherapy or cautious combination because of comorbidity.
Monitoring. Clinical review, six minute walk and NT-proBNP every 3 to 6 months, with risk reassessment 3 to 6 months after starting or changing therapy. Echocardiography every 6 to 12 months and right heart catheterisation with clinical change. Liver enzymes monthly and haemoglobin every 3 months on bosentan, haemoglobin and liver enzymes at baseline and as indicated on macitentan and ambrisentan, haemoglobin and platelets before the first doses of sotatercept, and creatinine and potassium with diuretics.
Referral and escalation. Refer to a pulmonary hypertension centre at diagnosis. Urgent for syncope, rising right atrial pressure, haemoptysis, pregnancy or pump failure on parenteral prostacyclin.
