What are the treatment options for a patient with pulmonary arterial hypertension (PAH), considering the World Health Organization (WHO) functional classification system and potential underlying conditions such as connective tissue disease or congenital heart disease?

PAH Classification and Treatment Options

WHO Functional Classification System

The WHO Functional Classification divides PAH patients into four classes based on symptom severity and physical activity limitations, which directly determines treatment intensity and predicts mortality risk. 1

• Class I: No limitation of physical activity; ordinary activity does not cause dyspnea, fatigue, chest pain, or near syncope 1
• Class II: Slight limitation of physical activity; ordinary activity causes symptoms 1
• Class III: Marked limitation of physical activity; less than ordinary activity causes symptoms 1
• Class IV: Unable to perform any physical activity without symptoms; dyspnea/fatigue present at rest 1

Risk Stratification Framework

Treatment decisions must be guided by comprehensive risk assessment, not functional class alone, with the goal of achieving and maintaining a low-risk profile. 2

Low-Risk Profile (Target for All Patients):

• WHO Functional Class I-II 2
• 6-minute walk distance >440 meters 2
• Normal or near-normal BNP/NT-proBNP levels 2
• No signs of right ventricular failure 2
• Estimated 1-year mortality <5% 2

Intermediate-Risk Profile:

• WHO Functional Class III 2
• 6-minute walk distance 165-440 meters 2
• Moderately elevated biomarkers 2
• Estimated 1-year mortality 5-10% 2

High-Risk Profile:

• WHO Functional Class III-IV with progression 2
• 6-minute walk distance <165 meters 2
• Severely elevated and rising BNP/NT-proBNP 2
• Signs of right ventricular failure 2
• Estimated 1-year mortality >10% 2

Initial Treatment Strategy

Step 1: General Measures and Supportive Therapy (All Patients)

All PAH patients must avoid pregnancy (Class I recommendation), receive influenza and pneumococcal vaccination, and have access to psychosocial support. 2

Supportive therapy includes:

• Diuretics: Indicated for all patients with right ventricular failure and fluid retention 2
• Oxygen therapy: Continuous supplementation when arterial oxygen pressure <60 mmHg (8 kPa) 2
• Anticoagulation with warfarin: Recommended for IPAH, heritable PAH, and anorexigen-associated PAH; should be considered for other PAH subtypes 2
• Supervised exercise rehabilitation: Should be considered for physically deconditioned patients already on medical therapy 2

Step 2: Vasoreactivity Testing and Initial Drug Therapy

All patients with IPAH must undergo acute vasoreactivity testing with short-acting agents (IV epoprostenol, adenosine, or inhaled nitric oxide) before initiating therapy. 2

For Vasoreactive Patients (Positive Test):

• Positive vasoreactivity: Fall in mean PAP ≥10 mmHg to ≤40 mmHg with increased or unchanged cardiac output 2
• Treatment: High-dose calcium channel blockers (CCBs) for vasoreactive patients without right heart failure 2
• Critical warning: CCBs must never be used empirically without documented vasoreactivity, as this can cause harm 2

For Non-Vasoreactive Patients (Majority):

Treatment selection depends on functional class and risk profile:

WHO Functional Class II (Low-Risk):

• Monotherapy with oral agents: Endothelin receptor antagonists (ERAs) or phosphodiesterase-5 inhibitors (PDE-5i) 3
• Specific options: Ambrisentan 5-10 mg daily 4 or sildenafil 2
• Goal: Maintain low-risk status with regular 3-6 month monitoring 3

WHO Functional Class III (Intermediate-Risk):

• Initial combination therapy preferred over monotherapy for most patients 2
• Oral combination: ERA + PDE-5i 2
• Alternative: Consider prostacyclin pathway agents if inadequate response 2

WHO Functional Class IV (High-Risk):

• Intravenous epoprostenol is the treatment of choice with the strongest evidence for mortality benefit in severe PAH 5
• Alternative: Intravenous treprostinil if epoprostenol not tolerated 6
• Goal: Rapid stabilization and improvement to lower risk category 5

Disease-Specific Considerations

PAH Associated with Connective Tissue Disease:

• Use the same treatment algorithm as IPAH (Class I recommendation) 2
• Anticoagulation: Consider on individual basis due to variable bleeding risk 2
• Note: CTD-PAH has higher mortality than IPAH, requiring aggressive treatment 7

PAH Associated with Congenital Heart Disease (Eisenmenger Syndrome):

• Bosentan is specifically indicated for WHO-FC III Eisenmenger patients (Class I, Level B) 2
• Other ERAs, PDE-5 inhibitors, and prostanoids should be considered (Class IIa) 2
• CCBs are contraindicated in Eisenmenger syndrome 2
• Anticoagulation: Consider only if PA thrombosis or heart failure present, and no significant hemoptysis 2
• Phlebotomy: Consider with isovolumic replacement when hematocrit >65% with hyperviscosity symptoms 2

PAH Associated with Portal Hypertension:

• Use same treatment algorithm as IPAH, accounting for comorbidities 2
• Anticoagulation is contraindicated due to increased bleeding risk 2
• Liver transplantation is contraindicated if mean PAP ≥35 mmHg or PVR ≥250 dynes·s·cm⁻⁵ 2

Treatment Escalation Strategy

If low-risk status is not achieved or maintained after 3-6 months, escalate therapy immediately. 3

Escalation Pathway:

1. From monotherapy: Add second oral agent (combination therapy) 3
2. From dual oral therapy: Add prostacyclin analog (triple therapy) 3
3. Refractory disease: Consider lung transplantation evaluation 5

Follow-Up Protocol

Reassess every 3-6 months in stable patients using multiple parameters simultaneously: 2

• WHO Functional Class 2
• 6-minute walk test 2
• BNP/NT-proBNP levels 2
• Echocardiography 2
• Consider repeat right heart catheterization at therapy initiation/changes 2

Critical Pitfalls to Avoid

• Never assume asymptomatic patients don't need treatment—low-risk patients still require therapy to maintain status 3
• Never use CCBs without positive vasoreactivity testing—this can worsen outcomes 2
• Never rely on single parameters—comprehensive risk assessment using multiple variables is mandatory 2
• Never delay referral to specialized centers—complex treatment decisions require expert management 2
• Never omit right heart catheterization—it is required to confirm diagnosis and guide therapy 2, 8