What are the treatment options for pulmonary arterial hypertension (PAH)?

Treatment and Identification of Pulmonary Arterial Hypertension (PAH)

Identification of PAH

PAH diagnosis requires a comprehensive evaluation to distinguish it from other forms of pulmonary hypertension and identify underlying causes. 1

Diagnostic Criteria and Classification

• PAH is defined as mean pulmonary artery pressure (PAP) ≥25 mmHg at rest 2
• PAH is classified as Group 1 pulmonary hypertension, which must be distinguished from:
  • Group 2: PH due to left heart disease
  • Group 3: PH due to lung diseases/hypoxia
  • Group 4: Chronic thromboembolic PH (CTEPH)
  • Group 5: PH with unclear mechanisms 1

Key Diagnostic Tests

• Right heart catheterization (essential for definitive diagnosis)
• Echocardiography (screening tool)
• Vasoreactivity testing to identify responders to calcium channel blockers 2
• A positive acute vasodilator response is defined as a fall in mean PAP of at least 10 mm Hg to ≤40 mm Hg with unchanged or increased cardiac output 2

Risk Assessment

Risk categories based on estimated 1-year mortality:

• Low risk (<5%): WHO FC I-II, 6MWD >440m, No RV dysfunction
• Intermediate risk (5-10%): WHO FC III, 6MWD 165-440m, Moderate RV dysfunction
• High risk (>10%): WHO FC IV, 6MWD <165m, Severe RV dysfunction 1

Treatment Algorithm for PAH

First-Line Therapy Based on Risk Assessment

For Low to Intermediate Risk Patients (WHO FC II-III):

1. Initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 inhibitor (PDE5i) is recommended as first-line treatment 2, 1

   • Preferred combinations include Ambrisentan + Tadalafil or Bosentan + Sildenafil 1

2. Monotherapy may be considered in specific situations:

   • Very mild PAH (WHO FC I)
   • Patients who cannot tolerate combination therapy
   • Patients with contraindications to combination therapy 1
   • Options include:
     • ERAs: Bosentan, Ambrisentan, or Macitentan
     • PDE5i: Sildenafil or Tadalafil
     • Soluble guanylate cyclase stimulator: Riociguat 2, 1

For High Risk Patients (WHO FC IV):

1. Intravenous epoprostenol is the treatment of choice 2, 3

   • Starting dose of 2 ng/kg/min with titration based on tolerance 1
   • Improves exercise capacity and survival in severe PAH 3

2. Alternative options if IV epoprostenol is not feasible:

   • Triple combination therapy with an ERA, PDE5i, and prostacyclin analogue 1
   • Other prostanoids: IV treprostinil, subcutaneous treprostinil, inhaled iloprost 2

Treatment for Patients with Inadequate Response to Initial Therapy

For patients who remain symptomatic despite initial therapy:

1. Escalate to triple combination therapy with an ERA, PDE5i, and prostacyclin analogue 2, 1
2. Consider adding:
   • Inhaled iloprost or treprostinil to oral therapy 2
   • Riociguat for patients on bosentan, ambrisentan, or inhaled prostanoid 2
   • Macitentan for patients on PDE5i or inhaled prostanoid 2

Supportive Measures

• Anticoagulation with warfarin for IPAH patients and those with indwelling catheters 2
• Diuretics for right ventricular failure with fluid retention 1
• Supplemental oxygen to maintain saturations >90% at all times 2, 1
• Supervised exercise training for deconditioned patients 1
• Immunizations against influenza and pneumococcal pneumonia 1

Special Considerations

Pregnancy

• Pregnancy should be avoided in PAH patients due to high maternal and fetal mortality risk (30-50%) 1
• Effective contraception is strongly recommended 1

Surgical Options

• Lung transplantation for patients with inadequate response to maximal medical therapy 2, 1
• Pulmonary endarterectomy for eligible CTEPH patients 1
• Balloon pulmonary angioplasty for inoperable CTEPH 1

Treatment Monitoring and Goals

• Regular follow-up assessments every 3-6 months 1
• Treatment goal is to achieve low-risk status (WHO FC II, 6MWD >440m) 1
• Consider referral to specialized centers for:
  • Inadequate response to maximal medical therapy
  • Need for complex combination therapy
  • High-risk features
  • Consideration for surgical options 1

Common Pitfalls and Caveats

1. Delayed diagnosis: PAH is often diagnosed late in its course when right ventricular failure has already developed. Early referral for unexplained dyspnea is crucial.

2. Inappropriate use of calcium channel blockers: Only patients with a positive acute vasoreactivity test should receive CCBs as primary therapy 2.

3. Inadequate dosing: Underdosing of medications is common due to side effects. Gradual titration to target doses is essential for optimal outcomes.

4. Failure to escalate therapy: Patients should be reassessed regularly, and therapy escalated promptly if treatment goals are not met 1.

5. Missing underlying causes: Always evaluate for underlying/associated disorders that may contribute to PAH, as treating these can significantly impact outcomes 2.

6. Lack of specialized care: Due to the complexity of PAH management, patients should be referred to specialized centers with expertise in PAH 2, 1.