What is the recommended treatment for a patient with pulmonary hypertension?

Treatment for Pulmonary Hypertension

Initial Assessment and Risk Stratification

For treatment-naïve patients with pulmonary arterial hypertension (PAH, WHO Group 1) at low or intermediate risk (WHO Functional Class II-III), initial oral combination therapy with ambrisentan 10 mg plus tadalafil 40 mg daily is recommended as first-line treatment, as this has proven superior to monotherapy in delaying clinical failure and improving outcomes. 1, 2

Before initiating therapy, all patients must undergo:

• Right heart catheterization to confirm PAH diagnosis and support treatment decisions 1
• Vasoreactivity testing during catheterization to identify the approximately 10% of patients who may respond to calcium channel blockers 1, 2
• Risk stratification using clinical assessment, exercise capacity (6-minute walk distance), biochemical markers, and hemodynamics 1, 2

Treatment Algorithm by Risk Category

Low to Intermediate Risk (WHO FC II-III)

For vasoreactive patients (positive acute vasoreactivity test):

• High-dose calcium channel blockers are recommended: long-acting nifedipine, diltiazem, or amlodipine (avoid verapamil due to negative inotropic effects) 2
• Close monitoring is essential—if patients do not improve to WHO FC I or II, additional PAH-specific therapy must be added 2

For non-vasoreactive patients (the majority):

• Initial combination therapy with ambrisentan plus tadalafil 40 mg daily is the preferred approach, demonstrating a median 6-minute walk distance improvement of 49 meters versus 24 meters with monotherapy (p<0.001) 1, 2, 3
• Alternative initial combination therapy may include other endothelin receptor antagonists (bosentan, macitentan) combined with phosphodiesterase-5 inhibitors 1
• If combination therapy is not tolerated, monotherapy with an endothelin receptor antagonist or PDE-5 inhibitor is acceptable, though less effective 1, 2

High Risk (WHO FC IV)

For high-risk patients, continuous intravenous epoprostenol should be prioritized as it is the only treatment proven to reduce 3-month mortality in this population. 1, 2, 4

• Initial combination therapy including IV prostacyclin analogues is recommended 1
• IV epoprostenol has established effectiveness in predominantly NYHA FC III-IV patients with idiopathic or heritable PAH 4

Sequential Combination Therapy

If inadequate clinical response occurs with initial therapy (defined as failure to achieve WHO FC I-II or 6-minute walk distance >440 meters), sequential double or triple combination therapy is recommended. 1, 2

The approach involves adding agents from different mechanistic pathways:

• Endothelin receptor antagonists (bosentan, ambrisentan, macitentan)
• Phosphodiesterase-5 inhibitors (sildenafil, tadalafil)
• Prostacyclin pathway agents (epoprostenol, treprostinil, iloprost, selexipag)
• Soluble guanylate cyclase stimulator (riociguat)

1

Critical Drug Interaction Warning

Riociguat must never be combined with PDE-5 inhibitors (sildenafil, tadalafil) due to severe risk of systemic hypotension—this combination is absolutely contraindicated. 2, 3

Supportive Care Measures

All PAH patients require comprehensive supportive management:

• Diuretics are indicated for signs of right ventricular failure and fluid retention 1, 2
• Continuous long-term oxygen therapy when arterial PO2 is consistently <60 mmHg (8 kPa) 1, 2
• Oral anticoagulation should be considered for idiopathic PAH, heritable PAH, and anorexigen-induced PAH 1, 2
• Supervised exercise rehabilitation for physically deconditioned patients 1, 2
• Immunization against influenza and pneumococcal pneumonia 2
• Pregnancy is absolutely contraindicated due to 30-50% maternal mortality risk 1, 2

Advanced and Rescue Therapies

Lung transplantation is recommended soon after inadequate clinical response on maximal medical therapy. 1, 2

• Both bilateral lung transplantation and heart-lung transplantation are options, with bilateral lung transplantation currently preferred 1
• Balloon atrial septostomy may be considered as a palliative or bridging procedure in patients deteriorating despite maximal therapy 1, 2

Monitoring and Follow-Up

Regular reassessment every 3-6 months for stable patients is essential, with more frequent monitoring for advanced disease. 1, 2

Assessment should include:

• WHO functional class
• 6-minute walk distance (target >440 meters)
• Echocardiographic evaluation
• Clinical signs of right heart failure

1, 2

Treatment for Other PH Groups

For Group 2 PH (left heart disease) and Group 3 PH (lung diseases), PAH-specific therapies are not recommended and may be harmful—treatment should focus on optimizing the underlying cardiac or pulmonary condition. 1, 2

For Group 4 PH (chronic thromboembolic pulmonary hypertension), surgical pulmonary endarterectomy in deep hypothermia circulatory arrest is the treatment of choice when feasible, with decisions made by a multidisciplinary expert team. 1, 2

Specialized Center Management

All PAH patients should be managed at specialized pulmonary hypertension centers with multidisciplinary teams including cardiology and respiratory medicine physicians, clinical nurse specialists, radiologists, and psychological support. 1, 2

Dosing Considerations

Selexipag (oral prostacyclin receptor agonist) is indicated to delay disease progression and reduce hospitalization risk, starting at 200 mcg twice daily and titrating weekly by 200 mcg increments to the highest tolerated dose up to 1,600 mcg twice daily. 5

For patients with moderate hepatic impairment (Child-Pugh B), reduce dosing frequency to once daily; avoid in severe hepatic impairment (Child-Pugh C) 5