Idiopathic Pulmonary Arterial Hypertension

Idiopathic pulmonary arterial hypertension (IPAH) is a progressive pre-capillary pulmonary vasculopathy with no identified cause, no family history and no exposure to a causative drug or toxin. It raises pulmonary vascular resistance, overloads the right ventricle and ends in right heart failure.

The haemodynamic definition at right heart catheterisation is mean pulmonary artery pressure over 20 mmHg, pulmonary artery wedge pressure of 15 mmHg or less, and pulmonary vascular resistance over 2 Wood units, once other causes are excluded.

About 2 to 6 new cases of pulmonary arterial hypertension arise in each million adults every year, and IPAH forms about 40 to 50% of registry cases. Women are affected 1.5 to 3 times more often than men. Older patients with obesity, hypertension, diabetes and a low diffusing capacity now make up a growing share.

Untreated median survival was under 3 years. With current treatment, 5-year survival is about 60 to 70%, and it depends on risk stratum at diagnosis and on the response to treatment.

About 10 to 20% of patients labelled idiopathic carry a germline variant, most often in BMPR2, so genetic counselling is offered.

Pathophysiology.

Endothelial dysfunction shifts the balance toward vasoconstriction and proliferation: raised endothelin-1 and thromboxane, and reduced prostacyclin and nitric oxide signalling.

Loss of BMPR2 signalling and imbalance within the transforming growth factor beta superfamily drive smooth muscle and endothelial proliferation, producing medial hypertrophy, intimal fibrosis, in situ thrombosis and plexiform lesions.

The right ventricle initially adapts with hypertrophy. Failure follows when afterload outstrips adaptation, with falling cardiac output, rising right atrial pressure, ischaemia and ventricular interdependence.

Exertional dyspnoea and fatigue are the earliest symptoms, with a delay of 2 years or more from onset to diagnosis being usual. Later features are exertional syncope or presyncope, chest pain, palpitations, abdominal distension and ankle oedema. Haemoptysis and hoarseness (Ortner syndrome) are uncommon.

Signs: loud pulmonary component of the second heart sound, right ventricular heave, right sided third or fourth heart sound, tricuspid regurgitation murmur, raised jugular venous pressure with prominent v waves, hepatomegaly, ascites and oedema.

• ECG: right axis deviation, right ventricular hypertrophy, P pulmonale, right bundle branch block. A normal ECG does not exclude disease.
• Echocardiography: tricuspid regurgitation velocity over 2.8 m/s, right atrial and ventricular enlargement, septal flattening, TAPSE under 17 mm, pericardial effusion, and signs of left heart disease.
• Pulmonary function tests with diffusing capacity, arterial blood gas, high resolution CT chest, and sleep study where indicated.
• Ventilation perfusion scan in every patient: a normal scan excludes chronic thromboembolic disease. Abnormal scans need CT pulmonary angiography and specialist review.
• Blood tests: NT-proBNP, full blood count, ferritin and transferrin saturation, liver tests, thyroid function, antinuclear antibody and specific antibodies, HIV test, hepatitis serology, and schistosomiasis serology where relevant.
• Right heart catheterisation is required for diagnosis. Record right atrial pressure, mean pulmonary artery pressure, wedge pressure, cardiac output and index, pulmonary vascular resistance and mixed venous saturation.
• Acute vasoreactivity test during catheterisation in IPAH: inhaled nitric oxide 10 to 20 ppm (alternatively intravenous epoprostenol or inhaled iloprost). A positive response is a fall in mean pulmonary artery pressure of 10 mmHg or more to under 40 mmHg with cardiac output unchanged or higher. About 5 to 10% of patients respond.
• Risk stratum (three bands, with annual mortality under 5%, 5 to 10%, and over 10%):
  • Low risk: functional class I or II, 6-minute walk over 440 m, NT-proBNP under 300 ng/L, right atrial pressure under 8 mmHg, cardiac index 2.5 L/min/m2 or more, mixed venous saturation over 65%.
  • Intermediate: class III, 165 to 440 m, NT-proBNP 300 to 1100 ng/L, right atrial pressure 8 to 14 mmHg, cardiac index 2.0 to 2.4, saturation 60 to 65%.
  • High: class IV, under 165 m, NT-proBNP over 1100 ng/L, right atrial pressure over 14 mmHg, cardiac index under 2.0, saturation under 60%, syncope, or progressive right heart failure.

Differential diagnosis.

• Pulmonary hypertension from left heart disease (heart failure with preserved ejection fraction, valve disease).
• Pulmonary hypertension from chronic lung disease and hypoxia, and chronic thromboembolic disease.
• Other forms of pulmonary arterial hypertension (connective tissue disease, HIV, portal hypertension, congenital shunts, drugs, schistosomiasis).
• Pulmonary veno occlusive disease (diffusing capacity under 50%, septal lines and lymph node enlargement on CT, pulmonary oedema with vasodilators), sarcoidosis, and pulmonary vasculitis.

General measures.

• Supervised exercise rehabilitation in stable patients. Avoid heavy exertion with syncope or chest pain. Avoid altitude over 1500 m without oxygen, and avoid pregnancy.
• Influenza, pneumococcal and COVID-19 vaccination. Early treatment of respiratory infection.
• Diuretics for congestion: furosemide 40 to 120 mg orally once or twice daily, titrated to dry weight, with spironolactone 25 to 100 mg daily (potassium under 5.0 mmol/L, eGFR over 30 mL/min/1.73 m2; check at 1 and 4 weeks). Avoid over diuresis because the right ventricle depends on preload.
• Long term oxygen for resting PaO2 under 8 kPa (60 mmHg).
• Correct iron deficiency (ferritin under 100 microgram/L or transferrin saturation under 20%): ferrous sulphate 200 mg orally once daily or on alternate days, or ferric derisomaltose 20 mg/kg (maximum 1000 mg) intravenously as a single infusion when oral therapy fails.
• Routine anticoagulation is not used because benefit is unproven and bleeding risk is real. Anticoagulate for atrial fibrillation, venous thromboembolism or thrombophilia.
• Beta blockers, ACE inhibitors and angiotensin receptor blockers have no role in the absence of left heart disease.

Vasoreactive patients. Calcium channel blocker only after a positive acute test: nifedipine modified release 30 to 60 mg twice daily titrated up to 240 mg daily, or diltiazem 60 mg three times daily titrated up to 720 mg daily, or amlodipine 5 to 20 mg daily. Avoid verapamil. Reassess at 3 to 4 months. Continue only with functional class I or II, mean pulmonary artery pressure under 30 mmHg and pulmonary vascular resistance under 4 Wood units. Otherwise add specific therapy.

Specific therapy. All drugs are continued long term.

• Initial therapy, low or intermediate risk: oral combination of an endothelin receptor antagonist with a phosphodiesterase-5 inhibitor.
  • Ambrisentan 5 mg orally once daily, increased to 10 mg once daily after 4 weeks (maximum 10 mg). Check haemoglobin and liver tests at baseline and when clinically indicated. Peripheral oedema and anaemia occur. Avoid in moderate to severe hepatic impairment.
  • Macitentan 10 mg orally once daily (maximum 10 mg). Check haemoglobin and ALT at baseline and when indicated. Avoid in severe hepatic impairment and with strong CYP3A4 inhibitors or inducers.
  • Bosentan 62.5 mg orally twice daily for 4 weeks, then 125 mg twice daily (maximum 250 mg daily; 62.5 mg twice daily when weight is under 40 kg). ALT and AST monthly. Contraindicated with ciclosporin and glibenclamide, and avoid in Child-Pugh B or C. It reduces the effect of hormonal contraceptives.
  • Tadalafil 40 mg orally once daily (start 20 mg once daily with mild to moderate renal or hepatic impairment; avoid when creatinine clearance is under 30 mL/min or in Child-Pugh C). Contraindicated with nitrates and riociguat.
  • Sildenafil 20 mg orally three times daily (maximum 20 mg three times daily as licensed for this indication). Contraindicated with nitrates and riociguat. Avoid with ritonavir.
  • All endothelin receptor antagonists are teratogenic: exclude pregnancy before starting and monthly afterwards, with effective contraception.
• Initial therapy, high risk: triple combination including parenteral prostacyclin.
  • Epoprostenol intravenously through a central line, starting at 2 ng/kg/min and increasing by 2 ng/kg/min at intervals of at least 15 minutes in hospital until dose limiting effects. Usual chronic dose is 20 to 40 ng/kg/min after 3 to 6 months. Never interrupt abruptly because of rebound pulmonary hypertension. Watch for line sepsis, jaw pain, diarrhoea, flushing and thrombocytopenia.
  • Treprostinil subcutaneously or intravenously, starting at 1.25 ng/kg/min (0.625 ng/kg/min in mild to moderate hepatic impairment), increased by 1.25 ng/kg/min weekly for 4 weeks, then by 2.5 ng/kg/min weekly. Infusion site pain is common with the subcutaneous route.
• Add on and escalation:
  • Selexipag 200 microgram orally twice daily, increased by 200 microgram twice daily each week to the highest tolerated dose (maximum 1600 microgram twice daily). In Child-Pugh B start 200 microgram once daily and increase weekly by 200 microgram once daily. Avoid in severe hepatic impairment and with strong CYP2C8 inhibitors (gemfibrozil).
  • Riociguat 1 mg orally three times daily (0.5 mg when hypotension risk is high), increased by 0.5 mg three times daily every 2 weeks if systolic pressure stays over 95 mmHg, to a maximum of 2.5 mg three times daily. Do not combine with phosphodiesterase-5 inhibitors or nitrates. Avoid when creatinine clearance is under 15 mL/min. Teratogenic.
  • Sotatercept 0.3 mg/kg subcutaneously, then 0.7 mg/kg every 3 weeks, added to background therapy in functional class II or III. Check haemoglobin and platelets before the first two doses and periodically; hold for a haemoglobin rise to excessive levels or platelets under 50 x 10^9/L. Watch for telangiectasia, epistaxis and bleeding. Avoid in pregnancy.
• Reassess risk at 3 to 6 months. If low risk is not reached, escalate (add selexipag or a prostacyclin, or switch a phosphodiesterase-5 inhibitor to riociguat, or add sotatercept).
• Older patients with several comorbidities and low risk may start with a phosphodiesterase-5 inhibitor alone.

Advanced disease. Refer for lung transplantation when risk is intermediate to high despite dual therapy, or high at diagnosis, without waiting for full escalation. Balloon atrial septostomy is a palliative bridge in selected patients with refractory syncope or right heart failure.

Right heart failure decompensation. Treat triggers (infection, arrhythmia, anaemia, non-adherence). Restore sinus rhythm. Diurese to a central venous pressure of about 8 to 12 mmHg. Use noradrenaline 0.05 to 0.5 microgram/kg/min for hypotension, dobutamine 2.5 to 10 microgram/kg/min for low output, and continue all pulmonary vasodilators without interruption.

Monitoring. Clinical review, functional class, 6-minute walk and NT-proBNP every 3 to 6 months. Echocardiography every 6 to 12 months. Right heart catheterisation at baseline, 3 to 6 months after treatment change, and with clinical deterioration. Haemoglobin and liver tests as set out for each drug. Pregnancy test monthly for women of childbearing potential.

Referral and escalation. Refer every patient with suspected or confirmed pulmonary hypertension to a pulmonary hypertension centre. Urgent referral for syncope, haemoptysis, rapid decline, high risk status, or need for parenteral therapy. Early referral for transplantation.

Special groups.

• Pregnancy: maternal mortality is about 20 to 30%, so pregnancy is advised against. Offer termination counselling. Use progestogen only implants or intrauterine devices (or two methods), and avoid oestrogen containing contraception. Endothelin receptor antagonists, riociguat and sotatercept are teratogenic.
• Older adults: comorbid phenotype, so exclude left heart disease before escalating, and use lower diuretic starting doses.
• Kidney or liver impairment: avoid ambrisentan in moderate to severe hepatic impairment, macitentan in severe hepatic impairment and bosentan in Child-Pugh B or C; start tadalafil at 20 mg daily in mild to moderate renal or hepatic impairment and avoid it at creatinine clearance under 30 mL/min or in Child-Pugh C; avoid riociguat at creatinine clearance under 15 mL/min; start selexipag at 200 microgram once daily in Child-Pugh B; give spironolactone only when eGFR is over 30 and potassium under 5.0 mmol/L.
• Region specific: exclude schistosomiasis, HIV, sickle cell disease, rheumatic valve disease and tuberculosis sequelae, which are frequent in sub-Saharan Africa. Access to specific therapy is limited, and sildenafil or tadalafil with diuretics is the most available option.