What is the classification and treatment approach for Pulmonary Arterial Hypertension (PAH)?

Classification and Treatment Approach for Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is classified as Group 1 in the clinical classification of pulmonary hypertension, with specific hemodynamic criteria requiring a mean pulmonary arterial pressure ≥25 mmHg at rest, pulmonary artery wedge pressure ≤15 mmHg, and pulmonary vascular resistance >3 Wood units. 1

Definition and Diagnostic Criteria

PAH is defined by specific hemodynamic parameters measured via right heart catheterization:

• Mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest
• Pulmonary artery wedge pressure (PAWP) ≤15 mmHg
• Pulmonary vascular resistance (PVR) >3 Wood units

These criteria distinguish PAH (pre-capillary pulmonary hypertension) from other forms of pulmonary hypertension. 1

Clinical Classification of PAH (Group 1)

PAH is classified into several subgroups based on etiology:

1. Idiopathic PAH (IPAH)

   • No identifiable cause

2. Heritable PAH (HPAH)

   • Associated with genetic mutations:
     • BMPR2 (bone morphogenetic protein receptor type 2)
     • ALK1 (activin receptor-like kinase 1)
     • Endoglin (with or without hereditary hemorrhagic telangiectasia)
     • Unknown mutations

3. Drug and Toxin-Induced PAH

4. Associated PAH (APAH)

   • Connective tissue diseases
   • HIV infection
   • Portal hypertension
   • Congenital heart disease
   • Schistosomiasis
   • Chronic hemolytic anemia

5. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH)

6. Persistent pulmonary hypertension of the newborn (PPHN) 1

Congenital Heart Disease Classification in PAH

PAH associated with congenital heart disease is further classified into:

1. Eisenmenger's syndrome

   • Large systemic-to-pulmonary shunts with severe PVR increase
   • Reversed or bidirectional shunting
   • Cyanosis, erythrocytosis, and multiple organ involvement

2. PAH associated with systemic-to-pulmonary shunts

   • Moderate to large defects
   • Mild to moderate PVR increase
   • Predominant systemic-to-pulmonary shunting
   • No cyanosis at rest

3. PAH with small defects

   • Small defects (VSD <1 cm, ASD <2 cm)
   • Clinical presentation similar to IPAH

4. PAH after corrective cardiac surgery

   • Persistent or recurrent PAH after surgical correction 1

Broader Classification of Pulmonary Hypertension

PAH is Group 1 within the broader 5-group classification of pulmonary hypertension:

1. Group 1: Pulmonary Arterial Hypertension (PAH)

   • As detailed above

2. Group 2: PH due to left heart disease

   • Systolic dysfunction
   • Diastolic dysfunction
   • Valvular disease

3. Group 3: PH due to lung diseases and/or hypoxemia

   • COPD
   • Interstitial lung disease
   • Sleep-disordered breathing
   • Alveolar hypoventilation disorders
   • Chronic high-altitude exposure
   • Developmental abnormalities

4. Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH)

5. Group 5: PH with unclear and/or multifactorial mechanisms

   • Hematological disorders
   • Systemic disorders
   • Metabolic disorders
   • Others 1

Treatment Approach for PAH

The treatment of PAH should be guided by risk stratification and targeted at improving survival and quality of life. The treatment approach includes:

1. General Measures

• Oral anticoagulation (targeting INR 1.5-2.5)
• Diuretics for fluid retention and right heart failure
• Oxygen supplementation when indicated
• Physical activity within symptom limits

2. PAH-Specific Therapy

First-line therapy should include combination therapy targeting multiple pathways simultaneously, which has shown improved morbidity and mortality compared to monotherapy. 2

PAH-specific medications include:

• Prostacyclin pathway agonists

  • Epoprostenol (IV): Indicated for PAH (WHO Group 1) to improve exercise capacity, particularly in NYHA Functional Class III-IV 3
  • Treprostinil (IV, SC, inhaled, oral)
  • Iloprost (inhaled)

• Endothelin receptor antagonists

  • Bosentan
  • Ambrisentan

• Phosphodiesterase-5 inhibitors

  • Sildenafil: Indicated for PAH (WHO Group 1) to improve exercise ability and delay clinical worsening 4
  • Tadalafil

• Soluble guanylate cyclase stimulators

  • Riociguat

3. Combination Therapy

Initial or sequential combination therapy targeting multiple pathways (e.g., ambrisentan and tadalafil) has demonstrated superior outcomes compared to monotherapy and is now the standard of care for most PAH patients. 2

4. Advanced Therapies

• Atrial septostomy
• Lung transplantation
• Pulmonary endarterectomy (for CTEPH)
• Balloon pulmonary angioplasty (for inoperable CTEPH)

Special Considerations

PAH Associated with Connective Tissue Disease

Patients with CTD-PAH have a higher mortality risk than IPAH and may require more aggressive initial therapy. Early screening is essential in high-risk CTD patients, particularly those with systemic sclerosis. 5, 6

PAH in Congenital Heart Disease

Treatment approach varies based on the specific subtype (Eisenmenger's syndrome vs. other forms). Specific considerations for shunt closure timing are critical to avoid worsening PAH. 1

Common Pitfalls to Avoid

1. Delayed diagnosis: Due to nonspecific early symptoms like dyspnea and fatigue, diagnosis is often delayed until advanced disease is present.

2. Inadequate hemodynamic assessment: Right heart catheterization is essential for definitive diagnosis and classification.

3. Monotherapy approach: Current evidence strongly supports initial combination therapy for most patients.

4. Failure to identify associated conditions: Always screen for underlying causes of PAH.

5. Inappropriate shunt closure: Closing cardiac shunts in patients with established PAH can worsen outcomes.

6. Inadequate follow-up: Regular risk assessment and treatment adjustments are necessary to optimize outcomes.