Idiopathic pulmonary arterial hypertension

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ONGOING

positive response to acute vasoreactivity testing with no contraindication to calcium-channel blockers

1st line – calcium-channel blocker trial

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1st line –

calcium-channel blocker trial

Acute vasoreactivity testing (with inhaled nitric oxide, inhaled iloprost, or intravenous epoprostenol) should generally be performed in all patients who would be candidates for calcium-channel blockers.[3] It is estimated that <10% of patients with IPAH are responders.[63] Vasoreactivity testing is contraindicated in patients with WHO functional class IV symptoms and low cardiac index. Vasoreactivity testing is generally not recommended for pulmonary hypertension that is caused by underlying diseases.

A positive response is defined as a fall in mean pulmonary artery pressure (mPAP) of ≥10 mmHg to reach an absolute value of ≤40 mmHg, with no decrease in cardiac output.[3][60] About 12% of patients are responsive, and they should be started on calcium-channel blocker therapy.[3][47]

Calcium-channel blockers predominantly used in pulmonary arterial hypertension are nifedipine, diltiazem, felodipine, and amlodipine.[3] Choice of drug can be based on baseline heart rate (HR): if HR <100 beats/minute - nifedipine, felodipine, or amlodipine; if HR >100 beats/minute - diltiazem.

A satisfactory response to a calcium-channel blocker is defined as being in functional class I or II with near-normal haemodynamics after several months of therapy.[3][47] Close monitoring is mandatory, and patients should have a full re-assessment at 3-6 months.[3]

Patients with a sustained satisfactory response should continue calcium-channel blocker therapy, with re-assessment every 6-12 months.[3]

Patients without a sustained satisfactory response require additional therapy and should be treated the same as those with a negative response to acute vasoreactivity testing (see below). Continuation of calcium-channel blocker (combined with additional therapy) may need to be considered in some patients because of clinical deterioration with calcium-channel blocker withdrawal attempts; consult a specialist.[3]

Primary options

nifedipine: 30 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 240 mg/day given in 1-2 divided doses

diltiazem: 40 mg orally (immediate-release) three times daily initially, increase gradually according to response, maximum 720 mg/day

felodipine: 5 mg orally once daily initially, increase gradually according to response, maximum 30 mg/day given in 1-2 divided doses

amlodipine: 5 mg orally once daily initially, increase gradually according to response, maximum 30 mg/day given in 1-2 divided doses

Plus – supportive measures

Back

Plus –

supportive measures

Treatment recommended for ALL patients in selected patient group

General supportive therapy is indicated for most patients.[3][35][56]

Supervised exercise training is recommended for those on pulmonary arterial hypertension medical therapy who are in a stable clinical condition.[3][57][58][59] [ ] Heavy physical exertion and isometric exercise should be avoided.[60] There is a lack of evidence for a direct impact of exercise training on survival and outcome in pulmonary hypertension. However, there are studies showing a beneficial effect on prognostically important parameters. The European Respiratory Society has identified a strong need to establish specialised rehabilitation programmes for patients with PAH to enhance access to this treatment intervention, which appears to be effective, cost-efficient and safe.[58]

Psychosocial support should be considered, including advanced care planning with referral to specialist palliative care services at the right time.[3]

Patients should be up to date with vaccinations and should be offered vaccinations for influenza, Streptococcus pneumoniae, and coronavirus disease 2019 (COVID-19) at a minimum.[3]

Patients with IPAH should avoid pregnancy, and women of child-bearing age should be counselled about the risks associated with becoming pregnant.[3][35] Those who present during pregnancy, or who become pregnant, should be treated by a multidisciplinary team experienced in managing pulmonary hypertension in pregnancy. Some of the drugs used to treat IPAH may cause fetal harm and may not be recommended in pregnancy; consult your local drug information source for more information.

Consider – diuretic

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Consider –

diuretic

Additional treatment recommended for SOME patients in selected patient group

A diuretic (e.g., furosemide) is recommended in patients with fluid retention and signs of right ventricular failure.[3][61][62] Effect on mortality is unknown.

Serum electrolytes and renal function should be closely monitored.[3][61] Excessive diuresis may lead to systemic hypotension, renal insufficiency, and syncope.

There are no trials with specific classes of diuretics, and thus the choice should be individualised according to local protocols.[3]

Primary options

furosemide: 20-80 mg orally initially, may repeat dose or increase by 20-40 mg every 6-8 hours according to response, usual dose 40-120 mg/day given in 1-2 divided doses, maximum 600 mg/day; 20-40 mg intravenously/intramuscularly initially, may repeat dose or increase by 20 mg every 2 hours according to response

Consider – supplemental oxygen

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Consider –

supplemental oxygen

Additional treatment recommended for SOME patients in selected patient group

Supplemental oxygen should be given in cases of hypoxaemia, defined as arterial oxygen tension of <60 mmHg or oxygen saturation of <92% at rest, during sleep, or with ambulation. Hypoxaemia is a potent pulmonary vasoconstrictor and can contribute to the development and/or progression of pulmonary arterial hypertension (PAH).

The goal of therapy is to keep oxygen saturation >92% at all times.[60] However, no consistent data are available on the effects of long-term oxygen treatment in PAH.[3] Thus, this recommendation is based on expert opinion and extrapolated from data in chronic obstructive pulmonary disease.

Consider – anticoagulation

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Consider –

anticoagulation

Additional treatment recommended for SOME patients in selected patient group

Patients with IPAH have in situ microscopic thrombosis in the pulmonary vasculature and prothrombotic abnormalities, and if in right ventricular failure, they are at increased risk for venous thromboembolism.[61] However, randomised controlled trial data on use of anticoagulation in patients with IPAH are lacking. Improved survival with anticoagulants has been reported in retrospective single-centre studies, one small prospective non-controlled non-randomised study, and one observational registry.[62][87] On the other hand, data from the REVEAL registry did not show a survival benefit from anticoagulation in IPAH patients.[88] Therefore, anticoagulation is not generally recommended in patients with pulmonary arterial hypertension but should be considered on a case-by-case basis.[3] Consult a specialist for guidance on the choice of anticoagulant regimen.

Consider – iron supplementation

Back

Consider –

iron supplementation

Additional treatment recommended for SOME patients in selected patient group

European guidelines recommend correction of iron status in patients with pulmonary arterial hypertension (PAH) and iron deficiency anaemia.[3] Randomised controlled trials comparing oral and intravenous iron supplementation in patients with PAH are lacking. European guidelines recommend intravenous supplementation for patients with severe iron deficiency anaemia (defined as haemoglobin <7-8 g/dL).[3] See Iron deficiency anaemia.

negative response to acute vasoreactivity testing or contraindication to calcium-channel blockers: without cardiopulmonary comorbidity

initially assessed as low or intermediate risk

1st line – endothelin receptor antagonist + phosphodiesterase-5 (PDE5) inhibitor

Back

1st line –

endothelin receptor antagonist + phosphodiesterase-5 (PDE5) inhibitor

Low- or intermediate-risk patients who are unresponsive to acute vasoreactivity testing, or who cannot take calcium-channel blockers, should be started on combination therapy with an endothelin receptor antagonist plus a PDE5 inhibitor.[3]

One multi-centre, randomised, double-blind, phase 3 study showed a lower risk of clinical failure with upfront combination therapy with ambrisentan plus tadalafil compared with each monotherapy alone.[80] In this study, upfront combination therapy with ambrisentan plus tadalafil delayed clinical worsening in pulmonary arterial hypertension (PAH), particularly hospitalisations. Another multi-centre, randomised, double-blind, phase 3b study demonstrated substantial improvements in haemodynamics and exercise capacity with initial endothelin receptor antagonist plus PDE5 inhibitor combination therapy (macitentan and tadalafil) and that there was no benefit of triple therapy (macitentan, tadalafil, and selexipag) compared with the double therapy.[81]

Endothelin receptor antagonists: ambrisentan has been shown to improve exercise capacity, symptoms, and haemodynamics and carries a low risk of liver toxicity.[68][69] Macitentan, a novel dual endothelin receptor antagonist, was found to delay a composite endpoint of morbidity and mortality (driven by worsening PAH symptoms) in a long-term event-driven placebo-controlled clinical trial.[70] Common adverse effects include anaemia, nasal congestion, and headache. Anaemia can occasionally be severe. Bosentan acts as an antagonist of both endothelin-A and endothelin-B receptors, and has shown improvements in the 6-minute walk distance (6MWD), functional class, haemodynamics, and time to clinical worsening. Liver function tests should be checked every month and haematocrit every 3 months. Bosentan is teratogenic in animals and may lessen the effectiveness of hormonal contraception. It may cause testicular atrophy and male infertility.[60]

PDE5 inhibitors: augment the pulmonary vascular response to nitric oxide.[71] Tadalafil has been shown to improve the 6MWD and to be associated with less clinical worsening and improved quality of life.[72] [ ] Sildenafil improves exercise capacity, functional class, and haemodynamics and may reduce clinical worsening.[73][74] There appears to be no dose-response relationship between higher doses of sildenafil and exercise capacity.[60]

European guidelines recommend initial oral combination therapy with tadalafil plus either ambrisentan or macitentan.[3] Combinations of other endothelin receptor antagonists and PDE5 inhibitors may also be considered. Proprietary combination fixed-dose formulations may be available in some countries (e.g., macitentan/tadalafil).

The European guidelines state that patients at intermediate risk presenting with severe haemodynamic impairment should be considered for initial triple therapy including a prostanoid (see patient group 'initially assessed as high risk', below, for details).

Primary options

ambrisentan: 5-10 mg orally once daily

macitentan: 10 mg orally once daily

-- AND --

tadalafil: 40 mg orally once daily

Secondary options

bosentan: body weight ≤40 kg: 62.5 mg orally twice daily; body weight >40 kg: 62.5 to 125 mg orally twice daily

and

tadalafil: 40 mg orally once daily

ambrisentan: 5-10 mg orally once daily

macitentan: 10 mg orally once daily

-- AND --

sildenafil: 20-80 mg orally three times daily; 10 mg intravenously every 8 hours

Plus – supportive measures

Back

Plus –

supportive measures

Treatment recommended for ALL patients in selected patient group

General supportive therapy is indicated for most patients.[3][35][56]

Supervised exercise training: recommended for those on PAH medical therapy who are in a stable clinical condition.[3][57][58][59] [ ] Heavy physical exertion and isometric exercise should be avoided.[60] There is a lack of evidence for a direct impact of exercise training on survival and outcome in pulmonary hypertension. However, there are studies showing a beneficial effect on prognostically important parameters. The European Respiratory Society has identified a strong need to establish specialised rehabilitation programmes for patients with PAH to enhance access to this treatment intervention, which appears to be effective, cost-efficient and safe.[58]

Psychosocial support should be considered, including advanced care planning with referral to specialist palliative care services at the right time.[3]

Patients should be up to date with vaccinations and should be offered vaccinations for influenza, Streptococcus pneumoniae, and coronavirus disease 2019 (COVID-19) at a minimum.[3]

Consider – sotatercept

Back

Consider –

sotatercept

Additional treatment recommended for SOME patients in selected patient group

Sotatercept, an activin signalling inhibitor, is approved in the US and Europe for the treatment of adults with pulmonary arterial hypertension to increase exercise capacity, improve WHO functional class, and reduce the risk of clinical worsening events. Addition of sotatercept to background therapy can be considered; however, guidelines do not yet recommend its use and there is no clear guidance on which patients should receive it. In one phase 2 trial, treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for PAH, compared with placebo.[78] In the multi-centre, double-blind, phase 3 STELLAR trial, in patients with PAH (WHO functional class II or III) on stable background therapy, adding sotatercept significantly improved exercise capacity (as assessed by the 6-minute walk test), compared with placebo.[79]

Sotatercept may cause serious bleeding (more likely with concomitant prostacyclin therapy and/or antithrombotic agents), erythrocytosis, and severe thrombocytopenia.

Primary options

sotatercept: 0.3 mg/kg subcutaneously every 3 weeks initially, increase to target dose of 0.7 mg/kg every 3 weeks according to response

Consider – diuretic

Back

Consider –

diuretic

Additional treatment recommended for SOME patients in selected patient group

A diuretic (e.g., furosemide) is recommended in patients with fluid retention and signs of right ventricular failure.[3][61][62] Effect on mortality is unknown.

Serum electrolytes and renal function should be closely monitored.[3][61] Excessive diuresis may lead to systemic hypotension, renal insufficiency, and syncope.

There are no trials with specific classes of diuretics, and thus the choice should be individualised according to local protocols.[3]

Primary options

Consider – supplemental oxygen

Back

Consider –

supplemental oxygen

Additional treatment recommended for SOME patients in selected patient group

Consider – anticoagulation

Back

Consider –

anticoagulation

Additional treatment recommended for SOME patients in selected patient group

Consider – iron supplementation

Back

Consider –

iron supplementation

Additional treatment recommended for SOME patients in selected patient group

initially assessed as high risk

1st line – endothelin receptor antagonist + phosphodiesterase-5 (PDE5) inhibitor + prostanoid

Back

1st line –

endothelin receptor antagonist + phosphodiesterase-5 (PDE5) inhibitor + prostanoid

High-risk patients who are unresponsive to acute vasoreactivity testing, or who cannot take calcium-channel blockers, should be considered for combination therapy with an endothelin receptor antagonist plus a PDE5 inhibitor plus a parenteral prostanoid (intravenous epoprostenol or intravenous/subcutaneous treprostinil).[3] Upfront triple therapy is associated with clinical and haemodynamic improvement and reduces right ventricular remodelling.[82][83][84]

Endothelin receptor antagonists: ambrisentan has been shown to improve exercise capacity, symptoms, and haemodynamics and carries a low risk of liver toxicity.[68][69] Macitentan, a novel dual endothelin receptor antagonist, was found to delay a composite endpoint of morbidity and mortality (driven by worsening pulmonary arterial hypertension [PAH] symptoms) in a long-term event-driven placebo-controlled clinical trial.[70] Common adverse effects include anaemia, nasal congestion, and headache. Anaemia can occasionally be severe. Bosentan acts as an antagonist of both endothelin-A and endothelin-B receptors, and has shown improvements in the 6-minute walk distance (6MWD), functional class, haemodynamics, and time to clinical worsening. Liver function tests should be checked every month and haematocrit every 3 months. Bosentan is teratogenic in animals and may lessen the effectiveness of hormonal contraception. It may cause testicular atrophy and male infertility.[60]

Prostanoids: shown to improve the distance walked in 6 minutes, functional class, and haemodynamics and to avoid clinical worsening.[3][64] [ ] Epoprostenol is administered via a continuous intravenous infusion (requiring an infusion pump and a permanent central venous catheter with associated risks of central venous catheter bloodstream infections). In one prospective, randomised, multi-centre trial, continuous intravenous infusion of epoprostenol improved symptoms, haemodynamics, and survival in patients with severe IPAH.[65] Treprostinil can be administered subcutaneously or intravenously. Subcutaneous administration of treprostinil avoids the risks associated with chronic indwelling central venous catheters, and in one double-blind, placebo-controlled multi-centre trial was shown to improve exercise capacity, symptoms, and haemodynamics in patients with PAH.[66]

Primary options

ambrisentan: 5-10 mg orally once daily

macitentan: 10 mg orally once daily

-- AND --

tadalafil: 40 mg orally once daily

-- AND --

epoprostenol: 2 nanograms/kg/minute intravenously initially, increase by 2 nanograms/kg/minute every 15 minutes according to response

treprostinil: 1.25 nanograms/kg/minute intravenously/subcutaneously initially, increase by 1.25 nanograms/kg/minute per week for the first 4 weeks and then by 2.5 nanograms/kg/minute per week for the remaining duration of the infusion according to response

Secondary options

bosentan: body weight ≤40 kg: 62.5 mg orally twice daily; body weight >40 kg: 62.5 to 125 mg orally twice daily

-- AND --

tadalafil: 40 mg orally once daily

-- AND --

epoprostenol: 2 nanograms/kg/minute intravenously initially, increase by 2 nanograms/kg/minute every 15 minutes according to response

ambrisentan: 5-10 mg orally once daily

macitentan: 10 mg orally once daily

-- AND --

sildenafil: 20-80 mg orally three times daily; 10 mg intravenously every 8 hours

-- AND --

epoprostenol: 2 nanograms/kg/minute intravenously initially, increase by 2 nanograms/kg/minute every 15 minutes according to response

Plus – supportive measures

Back

Plus –

supportive measures

Treatment recommended for ALL patients in selected patient group

General supportive therapy is indicated for most patients.[3][35][56]

Psychosocial support should be considered, including advanced care planning with referral to specialist palliative care services at the right time.[3]

Patients should be up to date with vaccinations and should be offered vaccinations for influenza, Streptococcus pneumoniae, and coronavirus disease 2019 (COVID-19) at a minimum.[3]

Consider – sotatercept

Back

Consider –

sotatercept

Additional treatment recommended for SOME patients in selected patient group

In one phase 2 trial, treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for PAH, compared with placebo.[78] In the multi-centre, double-blind, phase 3 STELLAR trial, in patients with PAH (WHO functional class II or III) on stable background therapy, adding sotatercept significantly improved exercise capacity (as assessed by the 6-minute walk test), compared with placebo.[79]

Sotatercept may cause serious bleeding (more likely with concomitant prostacyclin therapy and/or antithrombotic agents), erythrocytosis, and severe thrombocytopenia.

Primary options

sotatercept: 0.3 mg/kg subcutaneously every 3 weeks initially, increase to target dose of 0.7 mg/kg every 3 weeks according to response

Consider – diuretic

Back

Consider –

diuretic

Additional treatment recommended for SOME patients in selected patient group

A diuretic (e.g., furosemide) is recommended in patients with fluid retention and signs of right ventricular failure.[3][61][62] Effect on mortality is unknown.

Serum electrolytes and renal function should be closely monitored.[3][61] Excessive diuresis may lead to systemic hypotension, renal insufficiency, and syncope.

There are no trials with specific classes of diuretics, and thus the choice should be individualised according to local protocols.[3]

Primary options

Consider – supplemental oxygen

Back

Consider –

supplemental oxygen

Additional treatment recommended for SOME patients in selected patient group

Consider – anticoagulation

Back

Consider –

anticoagulation

Additional treatment recommended for SOME patients in selected patient group

Patients with IPAH have in situ microscopic thrombosis in the pulmonary vasculature and prothrombotic abnormalities, and if in right ventricular failure, they are at increased risk for venous thromboembolism.[61] However, randomised controlled trial data on use of anticoagulation in patients with IPAH are lacking. Improved survival with anticoagulants has been reported in retrospective single-centre studies, one small prospective non-controlled non-randomised study, and one observational registry.[62][87] On the other hand, data from the REVEAL registry did not show a survival benefit from anticoagulation in IPAH patients.[88] Therefore, anticoagulation is not generally recommended in patients with pulmonary arterial hypertension but should be considered on a case-by-case basis.[3] Consult a consultant for guidance on the choice of anticoagulant regimen.

Consider – iron supplementation

Back

Consider –

iron supplementation

Additional treatment recommended for SOME patients in selected patient group

assessed as low risk at follow-up

1st line – continue initial therapy

Back

1st line –

continue initial therapy

Patients should have regular follow-up (every 3-6 months according to patient needs). If they are assessed to be at low risk, they should continue their initial therapy.[3]

Switching from intravenous or subcutaneous therapy to oral therapy in a patient who achieves a low risk status can be considered on a case-by-case basis.

Plus – supportive measures

Back

Plus –

supportive measures

Treatment recommended for ALL patients in selected patient group

General supportive therapy is indicated for most patients.[3][35][56]

Psychosocial support should be considered, including advanced care planning with referral to specialist palliative care services at the right time.[3]

Patients should be up to date with vaccinations and should be offered vaccinations for influenza, Streptococcus pneumoniae, and coronavirus disease 2019 (COVID-19) at a minimum.[3]

Consider – diuretic

Back

Consider –

diuretic

Additional treatment recommended for SOME patients in selected patient group

A diuretic (e.g., furosemide) is recommended in patients with fluid retention and signs of right ventricular failure.[3][61][62] Effect on mortality is unknown.

Serum electrolytes and renal function should be closely monitored.[3][61] Excessive diuresis may lead to systemic hypotension, renal insufficiency, and syncope.

There are no trials with specific classes of diuretics, and thus the choice should be individualised according to local protocols.[3]

Primary options

Consider – supplemental oxygen

Back

Consider –

supplemental oxygen

Additional treatment recommended for SOME patients in selected patient group

Consider – anticoagulation

Back

Consider –

anticoagulation

Additional treatment recommended for SOME patients in selected patient group

Patients with IPAH have in situ microscopic thrombosis in the pulmonary vasculature and prothrombotic abnormalities, and if in right ventricular failure, they are at increased risk for venous thromboembolism.[61] However, randomised controlled trial data on use of anticoagulation in patients with IPAH are lacking. Improved survival with anticoagulants has been reported in retrospective single-centre studies, one small prospective non-controlled non-randomised study, and one observational registry.[62][87] On the other hand, data from the REVEAL registry did not show a survival benefit from anticoagulation in IPAH patients.[88] Therefore, anticoagulation is not generally recommended in patients with pulmonary arterial hypertension but should be considered on a case-by-case basis.[3] Consult a consultant for guidance on the choice of anticoagulant regimen.

Consider – iron supplementation

Back

Consider –

iron supplementation

Additional treatment recommended for SOME patients in selected patient group

assessed as intermediate-low risk at follow-up

1st line – endothelin receptor antagonist + phosphodiesterase-5 (PDE5) inhibitor + selexipag OR endothelin receptor antagonist + riociguat

Back

1st line –

endothelin receptor antagonist + phosphodiesterase-5 (PDE5) inhibitor + selexipag OR endothelin receptor antagonist + riociguat

Patients should have regular follow-up (every 3-6 months according to patient needs). If they are assessed to be at intermediate-low risk while on initial combination of an endothelin receptor antagonist and a PDE5 inhibitor, addition of selexipag to the regimen should be considered.

Alternatively, switching from the PDE5 inhibitor to riociguat may also be considered.[85] A PDE5 inhibitor and riociguat should not be used in combination, because this leads to a higher risk of systemic hypotension.[86]

Primary options

ambrisentan: 5-10 mg orally once daily

macitentan: 10 mg orally once daily

-- AND --

tadalafil: 40 mg orally once daily

-- AND --

selexipag: 200 micrograms orally twice daily initially, increased gradually according to response, maximum 3200 mg/day; 225-1800 micrograms intravenously twice daily

Secondary options

bosentan: body weight ≤40 kg: 62.5 mg orally twice daily; body weight >40 kg: 62.5 to 125 mg orally twice daily

and

tadalafil: 40 mg orally once daily

and

selexipag: 200 micrograms orally twice daily initially, increased gradually according to response, maximum 3200 mg/day; 225-1800 micrograms intravenously twice daily

ambrisentan: 5-10 mg orally once daily

macitentan: 10 mg orally once daily

-- AND --

sildenafil: 20-80 mg orally three times daily; 10 mg intravenously every 8 hours

-- AND --

selexipag: 200 micrograms orally twice daily initially, increased gradually according to response, maximum 3200 mg/day; 225-1800 micrograms intravenously twice daily

ambrisentan: 5-10 mg orally once daily

macitentan: 10 mg orally once daily

bosentan: body weight ≤40 kg: 62.5 mg orally twice daily; body weight >40 kg: 62.5 to 125 mg orally twice daily

-- AND --

riociguat: 0.5 to 2.5 mg orally three times daily

Plus – supportive measures

Back

Plus –

supportive measures

Treatment recommended for ALL patients in selected patient group

General supportive therapy is indicated for most patients.[3][35][56]

Psychosocial support should be considered, including advanced care planning with referral to specialist palliative care services at the right time.[3]

Patients should be up to date with vaccinations and should be offered vaccinations for influenza, Streptococcus pneumoniae, and coronavirus disease 2019 (COVID-19) at a minimum.[3]

Consider – sotatercept

Back

Consider –

sotatercept

Additional treatment recommended for SOME patients in selected patient group

Sotatercept may cause serious bleeding (more likely with concomitant prostacyclin therapy and/or antithrombotic agents), erythrocytosis, and severe thrombocytopenia.

It is important to note that there is a lack of data on the use of sotatercept in conjunction with selexipag and riociguat as part of background therapy. Consult a consultant for guidance and to discuss the potential risks and benefits of this combination therapy.

Primary options

sotatercept: 0.3 mg/kg subcutaneously every 3 weeks initially, increase to target dose of 0.7 mg/kg every 3 weeks according to response

Consider – diuretic

Back

Consider –

diuretic

Additional treatment recommended for SOME patients in selected patient group

A diuretic (e.g., furosemide) is recommended in patients with fluid retention and signs of right ventricular failure.[3][61][62] Effect on mortality is unknown.

Serum electrolytes and renal function should be closely monitored.[3][61] Excessive diuresis may lead to systemic hypotension, renal insufficiency, and syncope.

There are no trials with specific classes of diuretics, and thus the choice should be individualised according to local protocols.[3]

Primary options

Consider – supplemental oxygen

Back

Consider –

supplemental oxygen

Additional treatment recommended for SOME patients in selected patient group

Consider – anticoagulation

Back

Consider –

anticoagulation

Additional treatment recommended for SOME patients in selected patient group

Consider – iron supplementation

Back

Consider –

iron supplementation

Additional treatment recommended for SOME patients in selected patient group

assessed as intermediate-high or high risk at follow-up

1st line – endothelin receptor antagonist + phosphodiesterase-5 (PDE5) inhibitor + prostanoid

Back

1st line –

endothelin receptor antagonist + phosphodiesterase-5 (PDE5) inhibitor + prostanoid

Patients should have regular follow-up (every 3-6 months according to patient needs). If they are assessed to be at intermediate-high or high risk while on initial combination of an endothelin receptor antagonist plus a PDE5 inhibitor, addition of a parenteral prostanoid (epoprostenol or treprostinil) to the regimen should be considered.[86]

Primary options

ambrisentan: 5-10 mg orally once daily

macitentan: 10 mg orally once daily

-- AND --

tadalafil: 40 mg orally once daily

-- AND --

epoprostenol: 2 nanograms/kg/minute intravenously initially, increase by 2 nanograms/kg/minute every 15 minutes according to response

Secondary options

bosentan: body weight ≤40 kg: 62.5 mg orally twice daily; body weight >40 kg: 62.5 to 125 mg orally twice daily

-- AND --

tadalafil: 40 mg orally once daily

-- AND --

epoprostenol: 2 nanograms/kg/minute intravenously initially, increase by 2 nanograms/kg/minute every 15 minutes according to response

ambrisentan: 5-10 mg orally once daily

macitentan: 10 mg orally once daily

-- AND --

sildenafil: 20-80 mg orally three times daily; 10 mg intravenously every 8 hours

-- AND --

epoprostenol: 2 nanograms/kg/minute intravenously initially, increase by 2 nanograms/kg/minute every 15 minutes according to response

Plus – evaluation for lung transplant

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Plus –

evaluation for lung transplant

Treatment recommended for ALL patients in selected patient group

Referral for lung transplant evaluation is recommended when patients present with an inadequate response to optimised combination therapy and have an intermediate-high or high risk of death.[3] Double lung transplantation is most commonly performed. Heart-lung transplantation should be considered in patients with additional cardiac conditions.[3]

Plus – supportive measures

Back

Plus –

supportive measures

Treatment recommended for ALL patients in selected patient group

General supportive therapy is indicated for most patients.[3][35][56]

Psychosocial support should be considered, including advanced care planning with referral to specialist palliative care services at the right time.[3]

Patients should be up to date with vaccinations and should be offered vaccinations for influenza, Streptococcus pneumoniae, and coronavirus disease 2019 (COVID-19) at a minimum.[3]

Consider – sotatercept

Back

Consider –

sotatercept

Additional treatment recommended for SOME patients in selected patient group

Sotatercept may cause serious bleeding (more likely with concomitant prostacyclin therapy and/or antithrombotic agents), erythrocytosis, and severe thrombocytopenia.

Primary options

sotatercept: 0.3 mg/kg subcutaneously every 3 weeks initially, increase to target dose of 0.7 mg/kg every 3 weeks according to response

Consider – diuretic

Back

Consider –

diuretic

Additional treatment recommended for SOME patients in selected patient group

A diuretic (e.g., furosemide) is recommended in patients with fluid retention and signs of right ventricular failure.[3][61][62] Effect on mortality is unknown.

Serum electrolytes and renal function should be closely monitored.[3][61] Excessive diuresis may lead to systemic hypotension, renal insufficiency, and syncope.

There are no trials with specific classes of diuretics, and thus the choice should be individualised according to local protocols.[3]

Primary options

Consider – supplemental oxygen

Back

Consider –

supplemental oxygen

Additional treatment recommended for SOME patients in selected patient group

Consider – anticoagulation

Back

Consider –

anticoagulation

Additional treatment recommended for SOME patients in selected patient group

Consider – iron supplementation

Back

Consider –

iron supplementation

Additional treatment recommended for SOME patients in selected patient group

negative response to acute vasoreactivity testing or contraindication to calcium-channel blockers: with cardiopulmonary comorbidity

1st line – individualised therapy

Back

1st line –

individualised therapy

Evidence for treatment of patients with cardiopulmonary comorbidities is lacking. The European Society of Cardiology/European Respiratory Society guidelines recommend that initial monotherapy with an endothelin receptor antagonist or a phosphodiesterase-5 (PDE5) inhibitor may be considered, with additional treatment options considered on an individual basis for those at intermediate or high risk of death at follow-up.[3]

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Idiopathic pulmonary arterial hypertension

Treatment algorithm

positive response to acute vasoreactivity testing with no contraindication to calcium-channel blockers

calcium-channel blocker trial

Primary options

supportive measures

diuretic

Primary options

supplemental oxygen

anticoagulation

iron supplementation

negative response to acute vasoreactivity testing or contraindication to calcium-channel blockers: without cardiopulmonary comorbidity

endothelin receptor antagonist + phosphodiesterase-5 (PDE5) inhibitor

Primary options

Secondary options

supportive measures

sotatercept

Primary options

diuretic

Primary options

supplemental oxygen

anticoagulation

iron supplementation

endothelin receptor antagonist + phosphodiesterase-5 (PDE5) inhibitor + prostanoid

Primary options

Secondary options

supportive measures

sotatercept

Primary options

diuretic

Primary options

supplemental oxygen

anticoagulation

iron supplementation

continue initial therapy

supportive measures

diuretic

Primary options

supplemental oxygen

anticoagulation

iron supplementation

endothelin receptor antagonist + phosphodiesterase-5 (PDE5) inhibitor + selexipag OR endothelin receptor antagonist + riociguat

Primary options

Secondary options

supportive measures

sotatercept

Primary options

diuretic

Primary options

supplemental oxygen

anticoagulation

iron supplementation

endothelin receptor antagonist + phosphodiesterase-5 (PDE5) inhibitor + prostanoid

Primary options

Secondary options

evaluation for lung transplant

supportive measures

sotatercept

Primary options

diuretic

Primary options

supplemental oxygen

anticoagulation

iron supplementation

individualised therapy