How should pulmonary hypertension be treated, including diagnostic work‑up with right‑heart catheterisation and vasoreactivity testing, and specific therapy for WHO Groups 1, 4, and 5?

Treatment of Pulmonary Hypertension: Diagnostic Work-up and Specific Therapy

Right heart catheterization (RHC) must be performed at expert centers to confirm the diagnosis of WHO Group 1 PAH and guide treatment decisions, with vasoreactivity testing reserved exclusively for idiopathic PAH, heritable PAH, and drug-induced PAH to identify candidates for high-dose calcium channel blocker therapy. 1

Diagnostic Work-up with Right Heart Catheterization

Indications for RHC

RHC is mandatory (Class I recommendation) in the following scenarios:

• Group 1 (PAH): To confirm diagnosis and support all treatment decisions 1
• Group 4 (CTEPH): To confirm diagnosis and guide treatment planning 1
• Groups 2 and 3: When organ transplantation is being considered 1
• Congenital cardiac shunts: To support decisions regarding surgical correction 1

Critical procedural requirements:

• RHC must be performed at expert centers due to technical complexity and potential for serious complications 1
• When pulmonary artery wedge pressure (PAWP) is unreliable, left heart catheterization should be performed to measure left ventricular end-diastolic pressure (LVEDP) 1
• RHC should be considered to assess treatment response in Group 1 PAH patients already on therapy 1

Vasoreactivity Testing Protocol

Who Should Undergo Testing

Vasoreactivity testing is recommended ONLY for:

• Idiopathic PAH (IPAH) 1
• Heritable PAH (HPAH) 1
• PAH associated with drug/anorexigen use 1

Vasoreactivity testing is NOT recommended (Class III) for:

• PAH associated with connective tissue disease, HIV, portal hypertension, or congenital heart disease 1, 2
• WHO Groups 2,3,4, or 5 pulmonary hypertension 1, 2

Definition of Positive Response

A positive vasoreactivity response requires ALL of the following criteria:

• Reduction in mean pulmonary artery pressure (mPAP) ≥10 mmHg 1
• Absolute mPAP value ≤40 mmHg 1
• Increased or unchanged cardiac output 1

Preferred Testing Agents

First-line agents (Class I recommendation):

• Inhaled nitric oxide 1
• Intravenous epoprostenol 1

Alternative agents:

• Adenosine (Class IIa) 1
• Inhaled iloprost (Class IIb) 1

Contraindicated:

• Oral or intravenous calcium channel blockers during acute testing (Class III) 1

Specific Therapy for WHO Group 1 (PAH)

Calcium Channel Blocker Therapy

For vasoreactivity-positive patients:

• Only patients meeting strict positive response criteria should receive high-dose calcium channel blockers 1
• Approximately 10-15% of IPAH patients test positive, but only about half maintain long-term response 3, 4

Dosing regimens that have demonstrated efficacy:

• Nifedipine: 120-240 mg daily 1
• Diltiazem: 240-720 mg daily 1
• Amlodipine: up to 20 mg daily 1

Drug selection based on baseline heart rate:

• Relative bradycardia: nifedipine or amlodipine 1
• Relative tachycardia: diltiazem 1

Mandatory reassessment protocol:

• Repeat RHC at 3-4 months after initiating calcium channel blocker therapy 1
• Long-term response defined as: WHO functional class I or II with marked hemodynamic improvement 1
• If inadequate response: add PAH-specific therapy immediately 1
• Five-year survival is 98.5% in long-term responders versus 73.0% in non-responders 3

PAH-Specific Therapy for Non-Responders

For WHO functional class III patients who are not candidates for or have failed calcium channel blockers:

• Endothelin receptor antagonists (bosentan) 1
• Intravenous epoprostenol 1
• Subcutaneous treprostinil 1
• Inhaled iloprost 1
• Beraprost 1

Specific Therapy for WHO Group 4 (CTEPH)

Pulmonary thromboendarterectomy is the treatment of choice:

• All patients with suspected CTEPH must be referred to centers experienced in pulmonary endarterectomy 1
• RHC is mandatory to confirm diagnosis and assess operability 1
• Ventilation-perfusion scanning should be performed in all PAH patients to exclude CTEPH; a normal scan effectively rules out this diagnosis 1

Specific Therapy for WHO Group 5

The provided evidence does not contain specific treatment recommendations for WHO Group 5 pulmonary hypertension, as this heterogeneous category requires individualized management based on the underlying etiology.

Common Pitfalls and How to Avoid Them

Critical errors to avoid:

• Never perform vasoreactivity testing in congenital heart disease-associated PAH - it provides no clinically useful information and exposes patients to unnecessary risk 2
• Never use calcium channel blockers empirically without documented positive vasoreactivity testing - this can be harmful 1
• Never assume a positive acute vasoreactivity test guarantees long-term response - only 54.3% maintain sustained benefit 3
• Never skip the 3-4 month reassessment with repeat RHC after starting calcium channel blockers - early identification of non-responders is critical for survival 1, 3

Additional monitoring considerations:

• Pulmonary artery compliance at acute vasoreactivity testing, low-risk status, and NT-proBNP levels at early follow-up correlate with long-term response and predict survival 3