How should I treat an adult with World Health Organization Group 1 pulmonary arterial hypertension who is symptomatic (functional class II–III)?

Treatment of WHO Group 1 Pulmonary Arterial Hypertension (Functional Class II-III)

For symptomatic adults with WHO Group 1 PAH (functional class II-III), initial oral combination therapy with ambrisentan and tadalafil is recommended over monotherapy, as this approach has proven superior in delaying clinical failure and improving exercise capacity. 1, 2, 3

Initial Assessment and Risk Stratification

Before initiating therapy, all patients must undergo:

• Right heart catheterization to confirm diagnosis (mean PAP >20 mmHg, PAWP ≤15 mmHg, PVR >3 Wood units) and perform vasoreactivity testing 4, 5
• Systematic risk assessment using WHO functional class, 6-minute walk distance, BNP/NT-proBNP levels, echocardiographic findings, and hemodynamic parameters 1, 2
• Evaluation at an expert pulmonary hypertension center before starting treatment, ideally prior to therapy initiation 1

Treatment Algorithm for FC II-III Patients

Step 1: Determine Vasoreactivity Status

Vasoreactive patients (approximately 10% of idiopathic PAH):

• High-dose calcium channel blockers are first-line therapy for patients demonstrating acute vasoreactivity during right heart catheterization 1, 2, 3
• Use long-acting nifedipine (120-240 mg/day), diltiazem (240-720 mg/day), or amlodipine (up to 20 mg/day) 1
• Critical pitfall: Never start calcium channel blockers without documented positive vasoreactivity testing, as this can cause life-threatening hypotension and right ventricular ischemia 1, 4
• Reassess at 3-4 months with repeat right heart catheterization; if patient is not in WHO FC I-II with marked hemodynamic improvement, add PAH-specific therapy 1

Step 2: Non-Vasoreactive Patients (Majority)

Initial combination therapy is the standard of care:

• Ambrisentan plus tadalafil is recommended as first-line treatment for FC II-III patients 1, 2, 3, 6
• This combination targets two pathways (endothelin and nitric oxide-cGMP) and has demonstrated superiority over monotherapy in delaying time to clinical worsening 1, 5
• The 2019 CHEST guidelines gave this a weak recommendation with moderate quality evidence based on 6-minute walk test improvements, though the committee acknowledges that clinicians may prioritize the beneficial effect on delaying clinical worsening 1

Alternative monotherapy options (if combination therapy is not tolerated or feasible):

• Endothelin receptor antagonists: bosentan (125 mg twice daily) or ambrisentan 1, 2, 6
• Phosphodiesterase-5 inhibitors: sildenafil or tadalafil 1, 5
• Important monitoring: Bosentan requires liver function monitoring as hepatotoxicity occurs in approximately 10% of patients 2

Essential Supportive Care Measures

All PAH patients require:

• Diuretics for signs of right ventricular failure and fluid retention (Class I recommendation) 1, 4
• Supplemental oxygen when arterial oxygen pressure is consistently <60 mmHg (8 kPa) to maintain saturations >90% 1, 4
• Oral anticoagulation should be considered in idiopathic PAH, heritable PAH, and anorexigen-induced PAH (target INR 1.5-2.5) 1, 4
• Vaccination against influenza and pneumococcal pneumonia 1, 4
• Supervised exercise rehabilitation for physically deconditioned patients (Class IIa recommendation) 1
• Pregnancy avoidance is absolutely contraindicated due to 30-50% maternal mortality risk 1, 4
• Altitude precautions: avoid altitudes >1,500-2,000 meters without supplemental oxygen 2, 4

Monitoring and Treatment Goals

Regular follow-up every 3-6 months should include:

• WHO functional class assessment 1, 4
• 6-minute walk distance (target >440 meters, though >500 meters indicates low risk) 2, 4
• BNP/NT-proBNP levels (target <50 ng/L for low risk) 4
• Echocardiographic evaluation 1, 4

Primary therapeutic goal: Achieve and maintain WHO functional class I-II with supporting indicators including absence of right ventricular failure, stable or improving symptoms, no syncope, normal BNP levels, no pericardial effusion, right atrial pressure <8 mmHg, and cardiac index >2.5 L/min/m² 4

Sequential Escalation for Inadequate Response

If patients remain symptomatic or show clinical worsening on initial therapy:

• Add a second or third agent from a different drug class (prostacyclin analogue, soluble guanylate cyclase stimulator) 2, 4
• Contraindication: Never combine riociguat with phosphodiesterase-5 inhibitors due to hypotension risk 3, 4
• Consider continuous intravenous epoprostenol for patients deteriorating to high-risk status 2, 3

Advanced Therapies

• Lung transplantation should be considered after inadequate response to maximal combination therapy 2, 3, 4
• Balloon atrial septostomy may be considered as a palliative or bridging procedure in patients deteriorating despite maximal medical therapy 3, 4
• Palliative care services should be incorporated for symptom management, particularly in advanced disease 1, 2

Critical Pitfalls to Avoid

• Never start PAH-specific drugs without right heart catheterization confirmation of Group 1 PAH, as these medications can be harmful in Group 2 (left heart disease) PH 4
• Do not use calcium channel blockers empirically without documented vasoreactivity; only 10% of patients respond, and inappropriate use causes severe adverse effects 1, 2, 4
• Avoid excessive physical activity that leads to distressing symptoms, though supervised rehabilitation is beneficial 1
• Do not delay referral to specialized PH centers, as this results in inappropriate treatment and worse outcomes 2