What is the recommended treatment for pulmonary hypertension?

Treatment of Pulmonary Hypertension

The recommended treatment for pulmonary hypertension depends on the specific classification, with initial approved drugs monotherapy recommended in treatment-naïve, low or intermediate risk patients with pulmonary arterial hypertension, and initial approved oral drugs combination therapy recommended in treatment-naïve, low or intermediate risk patients. 1

Classification and Initial Assessment

Pulmonary hypertension (PH) is classified into five groups, with treatment strategies differing significantly between them:

• Group 1: Pulmonary arterial hypertension (PAH)
• Group 2: PH due to left heart disease
• Group 3: PH due to lung diseases and/or hypoxemia
• Group 4: Chronic thromboembolic PH (CTEPH)
• Group 5: PH with unclear/multifactorial mechanisms

Before initiating treatment, patients should undergo:

• Acute vasoreactivity testing (for Group 1 PAH patients)
• Risk assessment based on clinical evaluation, exercise tests, biomarkers, and hemodynamic parameters

Treatment Algorithm by PH Classification

Group 1: Pulmonary Arterial Hypertension (PAH)

1. General Measures:

   • Avoid pregnancy (Class I recommendation) 1
   • Immunization against influenza and pneumococcal infection (Class I) 1
   • Supervised exercise rehabilitation for deconditioned patients (Class IIa) 1
   • Psychosocial support (Class I) 1
   • Avoid excessive physical activity that causes distressing symptoms 1

2. Supportive Therapy:

   • Diuretics for right ventricular failure and fluid retention 1
   • Long-term oxygen therapy when arterial blood O₂ pressure is consistently <8 kPa (60 mmHg) 1
   • Oral anticoagulants should be considered in idiopathic PAH, heritable PAH, and anorexigen-induced PAH 1

3. Specific PAH Therapy:

   • For vasoreactive patients: High-dose calcium channel blockers 2

   • For non-vasoreactive patients:

     • Low/Intermediate Risk:

       • Initial monotherapy options: endothelin receptor antagonists (bosentan, ambrisentan), PDE-5 inhibitors (sildenafil, tadalafil), or soluble guanylate cyclase stimulator (riociguat) 2
       • Initial oral combination therapy (e.g., ambrisentan plus tadalafil) has shown superiority to monotherapy 2

     • High Risk:

       • Initial combination therapy including IV prostacyclin analogs (e.g., epoprostenol) 2

     • Inadequate Response:

       • Sequential combination therapy (adding a second or third drug from a different class) 1, 2
       • Note: Combination of riociguat and PDE-5 inhibitors is contraindicated 2

4. Follow-up and Monitoring:

   • Regular assessment every 3-6 months including exercise capacity, WHO functional class, hemodynamic parameters, and BNP/NT-proBNP levels 1, 2
   • Consider lung transplantation for patients with inadequate response to medical therapy 1

Group 2: PH due to Left Heart Disease

• Focus on treating the underlying heart disease
• PAH-specific medications are not recommended (Class III recommendation) 1

Group 3: PH due to Lung Diseases and/or Hypoxemia

• Treat the underlying lung disease
• Long-term oxygen therapy for chronic hypoxemia
• PAH-specific medications are not recommended (Class III recommendation) 1

Group 4: Chronic Thromboembolic PH (CTEPH)

• Lifelong anticoagulation (Class I recommendation) 1
• Surgical pulmonary endarterectomy is the recommended treatment (Class I) 1
• For inoperable patients or those with residual PH after surgery, PAH-specific drug therapy may be considered 1

Important Clinical Considerations

• Drug Interactions: Monitor for significant interactions when using PAH medications, particularly with CYP3A4 inhibitors/inducers 1, 3
• Hepatotoxicity: Regular monitoring of liver function is required with certain PAH therapies, especially bosentan 3, 4
• Abrupt Withdrawal: Never abruptly discontinue prostacyclin therapy as it can lead to rebound PH and death 2
• Delayed Treatment Escalation: Increases mortality risk; consider early combination therapy for patients not adequately responding to monotherapy 2

Evidence for Specific Treatments

Bosentan, a dual endothelin receptor antagonist, has demonstrated efficacy in improving exercise capacity and hemodynamics in PAH patients 5. The BREATHE study showed a 44m improvement in 6-minute walking distance compared to placebo 5. Bosentan is generally well tolerated at the approved dosage of 125mg twice daily, though it carries risks of hepatotoxicity and teratogenicity 4.

The treatment approach should be regularly reassessed based on clinical response, with combination therapy considered for patients with inadequate response to initial therapy.