Pulmonary Hypertension Drugs

Pulmonary hypertension drugs lower pulmonary vascular resistance and slow vascular remodelling in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary hypertension is a mean pulmonary artery pressure over 20 mmHg at rest on right heart catheterisation. Pre-capillary disease also has a wedge pressure of 15 mmHg or less and a pulmonary vascular resistance over 2 Wood units. These drugs are for pre-capillary disease only and can harm in left heart or lung disease.

Disease groups. Group 1 PAH (idiopathic, heritable, drug or toxin induced, connective tissue disease, HIV, portal hypertension, congenital heart disease, schistosomiasis); group 2 left heart disease; group 3 lung disease or hypoxia; group 4 CTEPH; group 5 multifactorial causes, including sickle cell disease.

Drug classes. Endothelin receptor antagonists (bosentan, ambrisentan, macitentan); phosphodiesterase 5 inhibitors (sildenafil, tadalafil); a soluble guanylate cyclase stimulator (riociguat); prostacyclin analogues and an IP receptor agonist (epoprostenol, treprostinil, iloprost, selexipag); an activin signalling inhibitor (sotatercept). High dose calcium channel blockers apply only to the small group with a positive vasoreactivity test.

Mechanism. Endothelin drives vasoconstriction and proliferation, and receptor antagonists block it. Nitric oxide and cyclic GMP cause vasodilation, boosted by phosphodiesterase 5 inhibitors and guanylate cyclase stimulators. Prostacyclin and cyclic AMP cause vasodilation and inhibit platelets and proliferation, and are replaced or stimulated. Sotatercept traps activins and growth factors and restores balance in BMPR2 signalling.

Representative doses.

• Sildenafil 20 mg three times daily; tadalafil 40 mg once daily.
• Bosentan 62.5 mg twice daily for 4 weeks, then 125 mg twice daily; ambrisentan 5 mg once daily, up to 10 mg; macitentan 10 mg once daily.
• Riociguat 1 mg three times daily, titrated every 2 weeks to a maximum of 2.5 mg three times daily.
• Selexipag 200 mcg twice daily, titrated weekly to a maximum of 1600 mcg twice daily.
• Sotatercept 0.3 mg/kg subcutaneously every 3 weeks, then 0.7 mg/kg every 3 weeks from the second dose if tolerated.

Differences. An endothelin receptor antagonist with tadalafil is the usual first combination. Prostacyclins are reserved for high risk disease. Riociguat and phosphodiesterase 5 inhibitors must never be combined.

Before specific therapy. Confirm the diagnosis by right heart catheterisation, identify the group and treat the cause (schistosomiasis, HIV, sickle cell disease, thromboembolism). Specific drugs are not advised in group 2 or group 3 disease, except inhaled treprostinil in interstitial lung disease with pulmonary hypertension.

Vasoreactivity test. Done at catheterisation with inhaled nitric oxide in idiopathic, heritable and drug induced PAH only. A positive result is a fall in mean pressure of 10 mmHg or more to 40 mmHg or less with unchanged or higher cardiac output, which occurs in about 5 to 10 percent. Responders take a high dose calcium channel blocker: nifedipine 120 to 240 mg daily, diltiazem 240 to 720 mg daily or amlodipine up to 20 mg daily. Reassess at 3 to 4 months and add specific drugs if functional class remains III or worse.

Risk stratification. Estimated 1 year mortality is under 5 percent (low), 5 to 20 percent (intermediate) or over 20 percent (high). It is judged from functional class, 6 minute walk distance (low risk over 440 m, high risk under 165 m), NT-proBNP (low under 300 ng/L, high over 1400 ng/L) and haemodynamics. Reassess every 3 to 6 months.

Treatment steps.

• Low or intermediate risk: an endothelin receptor antagonist (ambrisentan or macitentan) with tadalafil as initial combination. Monotherapy only for patients who cannot take combination therapy.
• High risk: triple therapy including intravenous or subcutaneous prostacyclin (epoprostenol or treprostinil), with early assessment for lung transplantation.
• Inadequate response at 3 to 6 months: add a third class (selexipag, a prostacyclin or sotatercept).
• CTEPH: pulmonary endarterectomy if operable. Riociguat 1 mg three times daily, titrated to 2.5 mg three times daily, for inoperable or persistent disease. Lifelong anticoagulation.

Supportive treatment. Diuretic for right heart failure, oxygen when saturation is under 90 percent or arterial oxygen is under 8 kPa (60 mmHg), correction of iron deficiency, vaccination against influenza and pneumococcus, supervised exercise and effective contraception. Anticoagulation is not routine in PAH.

Region. In East Africa schistosomiasis, sickle cell disease, HIV, rheumatic mitral valve disease and chronic lung disease are common causes, and many cases are group 2 or group 3, where specific drugs do not help. Generic sildenafil is often the only specific drug available. Confirm the group before treating, and refer for catheterisation where possible.

Embryo-foetal toxicity. Endothelin receptor antagonists and riociguat are contraindicated in pregnancy. Exclude pregnancy before starting and every month. This is a boxed-warning level risk.

Hypotension. Phosphodiesterase 5 inhibitors and riociguat with nitrates cause severe hypotension and are contraindicated.

Bleeding. Riociguat and prostacyclins cause haemoptysis and epistaxis, and sotatercept causes telangiectasia, epistaxis, raised haemoglobin and thrombocytopenia.

Interactions. Bosentan induces CYP3A4 and lowers sildenafil, hormonal contraceptives, warfarin and simvastatin levels. Ritonavir and azole antifungals raise macitentan, riociguat and sildenafil levels. Rifampicin lowers macitentan and sildenafil exposure and is usually avoided.

Monitoring. Functional class, 6 minute walk distance, NT-proBNP, oxygen saturation, echocardiography, haemoglobin, liver tests monthly with bosentan, monthly pregnancy tests and blood pressure.

Special groups.

• Pregnancy: PAH carries high maternal mortality, so pregnancy is advised against. If pregnancy occurs, stop endothelin receptor antagonists and riociguat, and manage with sildenafil, a prostacyclin and anticoagulation in a specialist centre.
• Breastfeeding: avoid endothelin receptor antagonists and riociguat.
• Children: weight-based specialist dosing.
• Older adults: start low and watch for hypotension.
• Hepatic impairment: avoid bosentan in Child-Pugh B or C.
• Renal impairment: avoid riociguat when creatinine clearance is under 15 mL/min and tadalafil when under 30 mL/min.

Referral and escalation. All patients need a specialist pulmonary hypertension centre. Syncope, rising NT-proBNP, right heart failure or functional class IV needs urgent admission and review for intravenous prostacyclin.