What are the treatment options for Pulmonary Arterial Hypertension (PAH)?

Treatment Options for Pulmonary Arterial Hypertension (PAH)

Initial combination therapy with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 inhibitor (PDE5i) is recommended as first-line treatment for most patients with PAH, while intravenous epoprostenol is the treatment of choice for high-risk or WHO Functional Class IV patients. 1

Risk Assessment and Treatment Algorithm

Treatment decisions should be guided by a comprehensive risk assessment:

Risk Stratification

Risk Category	Estimated 1-year Mortality	Key Features
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

Treatment Based on Functional Class

WHO Functional Class I-II (Low Risk)

1. First-line therapy options:

   • Ambrisentan (ERA) to improve 6-minute walk distance 2
   • Bosentan (ERA) to delay time to clinical worsening 2
   • Macitentan (ERA) to delay time to clinical worsening 2
   • Sildenafil (PDE5i) to improve 6-minute walk distance 2
   • Tadalafil (PDE5i) to improve 6-minute walk distance 2
   • Riociguat (soluble guanylate cyclase stimulator) to improve 6MWD, WHO FC, delay clinical worsening 2

2. Initial combination therapy with an ERA and PDE5i is increasingly preferred over monotherapy 1

WHO Functional Class III (Intermediate Risk)

1. Oral combination therapy:

   • ERA (ambrisentan, bosentan, macitentan) + PDE5i (sildenafil, tadalafil)
   • Consider adding riociguat if on bosentan or ambrisentan (note: riociguat should not be combined with PDE5i due to hypotension risk) 1

2. Consider adding prostacyclin pathway agents if inadequate response to dual therapy:

   • Inhaled iloprost or treprostinil
   • Subcutaneous treprostinil
   • Oral selexipag

WHO Functional Class IV (High Risk)

1. Intravenous epoprostenol is the treatment of choice, starting at 2 ng/kg/min and titrating to dose-limiting effects 1, 3
2. Alternative options:
   • IV treprostinil
   • Triple combination therapy (ERA + PDE5i + prostacyclin analogue) 1

Specific Medication Classes

Endothelin Receptor Antagonists (ERAs)

• Ambrisentan: Start at 5 mg daily, increase to 10 mg if tolerated 2
• Bosentan: 125 mg twice daily (higher doses associated with increased transaminase elevation) 2
• Macitentan: Delays time to clinical worsening 2

PDE5 Inhibitors

• Sildenafil: FDA-approved dose is 20 mg three times daily; may consider increasing to 80 mg three times daily if inadequate response 2, 4
• Tadalafil: Improves 6-minute walk distance 2

Prostacyclin Pathway Agents

• Epoprostenol (IV): First-line for FC IV patients; improves exercise capacity in NYHA Class III-IV symptoms 3
• Treprostinil: Available in IV, subcutaneous, inhaled, and oral formulations
• Iloprost: Inhaled formulation

Soluble Guanylate Cyclase Stimulator

• Riociguat: Improves 6MWD, WHO FC, delays clinical worsening 2
• Cannot be combined with PDE5i due to hypotension risk 2

Supportive Therapies

1. Anticoagulation:

   • Warfarin (target INR 1.5-2.5) recommended for idiopathic PAH and patients with indwelling catheters 2, 1
   • Consider risk/benefit in PAH associated with other conditions (e.g., scleroderma, congenital heart disease) 2

2. Oxygen therapy:

   • Maintain oxygen saturations >90% at all times 2, 1

3. Diuretics:

   • Indicated for right ventricular failure with peripheral edema/ascites 2
   • Careful monitoring to avoid excessive diuresis leading to systemic hypotension

4. Other supportive measures:

   • Immunization against influenza and pneumococcal pneumonia 2
   • Aggressive treatment of respiratory infections 2
   • Supervised exercise training for deconditioned patients 1

Treatment Escalation

For patients who remain symptomatic despite initial therapy:

1. Escalate to triple combination therapy (ERA + PDE5i + prostacyclin analogue) 1
2. Consider lung transplantation for inadequate response to maximal medical therapy 1

Special Considerations

• Pregnancy: Should be avoided due to high maternal and fetal mortality risk (30-50%) 1
• Vasoreactivity testing: Patients with positive acute vasodilator response may benefit from calcium channel blockers 2, 1
• Regular follow-up: Every 3-6 months, with treatment goals aimed at achieving low-risk status 1

Common Pitfalls and Caveats

1. Misclassification of PH type: Ensure proper diagnosis of Group 1 PAH versus other forms of PH (Groups 2-5), as treatment differs significantly 1, 5

2. Inadequate dosing: Although FDA-approved dose of sildenafil is 20 mg TID, clinical trials have used up to 80 mg TID with dose-dependent hemodynamic responses 2, 4

3. Drug interactions: Avoid combining riociguat with PDE5 inhibitors due to hypotension risk 2, 1

4. Delayed escalation: Failure to escalate therapy promptly when treatment goals are not met can lead to disease progression 1

5. Overlooking supportive care: Anticoagulation, oxygen therapy, and diuretics remain important components of comprehensive management 2, 1