What is the recommended diagnostic workup and management strategy for pulmonary hypertension, including WHO group classification and appropriate therapies?

Pulmonary Hypertension: Diagnostic Workup and Management

Diagnostic Confirmation

Right heart catheterization is mandatory before initiating any PAH-specific therapy to confirm the diagnosis and establish WHO group classification 1, 2, 3. Do not start PAH-specific drugs empirically based on echocardiography alone, as this can delay appropriate treatment and cause harm, particularly in Group 2 PH (left heart disease) 2.

Initial Diagnostic Workup

When echocardiography shows RVSP >45 mmHg with symptoms suggesting PH, initiate comprehensive evaluation 1:

• Laboratory studies: CBC, comprehensive metabolic panel, thyroid function, NT-proBNP, hepatitis serologies, HIV, hypercoagulable panel when indicated 1
• Autoimmune screening: If ANA positive, check anti-dsDNA, anti-scl-70, anti-centromere, anti-RNP, anti-SSA, anti-SSB 1
• Imaging: Chest X-ray, ECG, non-contrast chest CT or CT angiogram if thromboembolism suspected, V/Q scan 1
• Functional assessment: Pulmonary function tests with DLCO, 6-minute walk test 1
• Definitive diagnosis: Right heart catheterization with vasoreactivity testing in idiopathic, heritable, or drug-induced PAH 1, 2, 4

Vasoreactivity Testing

Perform vasoreactivity testing during right heart catheterization in all patients with idiopathic, heritable, or drug-induced PAH 1, 2, 4. A positive response is defined as a fall in mean PAP ≥10 mmHg to ≤40 mmHg with increased or unchanged cardiac output 4. This identifies the small subset (~10%) who can be treated with high-dose calcium channel blockers 4.

WHO Group Classification and Treatment Strategy

Group 1: Pulmonary Arterial Hypertension

Risk stratification determines initial therapy selection 2, 3, 4. Assess using WHO functional class, 6-minute walk distance, BNP/NT-proBNP, right atrial pressure, and cardiac index 4.

Vasoreactive Patients (Positive Acute Vasodilator Response)

• High-dose calcium channel blockers are first-line therapy 1, 2, 4
• Use nifedipine or diltiazem titrated to optimally tolerated doses 4

Non-Vasoreactive Patients

Low or Intermediate Risk:

• Initial oral combination therapy with ambrisentan plus tadalafil is recommended as it has proven superior to monotherapy in delaying clinical failure 1, 2, 3
• Alternative: Initial monotherapy with endothelin receptor antagonists or phosphodiesterase-5 inhibitors 1, 5

High Risk (WHO FC IV, low cardiac index, high right atrial pressure):

• Prioritize intravenous epoprostenol as it reduces 3-month mortality in high-risk patients 1, 2, 3
• Consider initial combination therapy including IV prostacyclin analogues 1, 2

Sequential Combination Therapy

If inadequate response to initial therapy, escalate to sequential double or triple combination therapy targeting multiple pathways 1, 3. Do not combine riociguat with PDE-5 inhibitors (contraindicated) 1.

Group 2: Left Heart Disease

PAH-specific therapies are not recommended and may be harmful 1, 2, 3. Focus on optimizing management of underlying left heart disease.

Group 3: Lung Disease

PAH-approved therapies are not recommended for PH due to lung disease 1. Long-term oxygen therapy to maintain saturations >90% is the primary treatment and partially reduces PH progression 2. Severe PH (mean PAP ≥35 mmHg) with lung disease does not respond well to vasodilator therapy, particularly in interstitial lung disease and emphysema phenotypes 6.

Group 4: Chronic Thromboembolic Pulmonary Hypertension

Surgical pulmonary endarterectomy in deep hypothermia circulatory arrest is the treatment of choice 1, 2, 3. Assessment of operability must be made by a multidisciplinary expert team 1. For inoperable CTEPH or persistent/recurrent PH after surgery, riociguat is recommended 3. Lifelong anticoagulation targeting INR 2-3 is mandatory 2, 3.

Essential Supportive Care

All PAH patients require comprehensive supportive measures 2, 3:

• Diuretics: For all patients with right ventricular failure and fluid retention 2
• Oxygen: Continuous supplementation when arterial oxygen pressure <60 mmHg or to maintain saturations >90% 2, 3
• Anticoagulation: Consider in idiopathic PAH, heritable PAH, and anorexigen-induced PAH, targeting INR 1.5-2.5 2
• Pregnancy avoidance: Mandatory due to 30-50% mortality risk 1, 3
• Supervised exercise training: For physically deconditioned patients 3

Monitoring and Treatment Goals

Perform regular assessments every 3-6 months in stable patients 1, 3, 4. Evaluate:

• WHO functional class
• 6-minute walk distance (target >440 meters for most patients) 2
• BNP/NT-proBNP levels 1, 4
• Echocardiographic parameters 1, 4

The primary goal is achieving and maintaining low-risk status (WHO FC I-II, good exercise capacity, preserved RV function) 2, 3, 4.

Advanced Therapies

Consider eligibility for lung transplantation after inadequate response to initial monotherapy or combination therapy 1, 2, 3. Refer for transplantation soon after inadequate response is confirmed on maximal combination therapy 1, 2. Balloon atrial septostomy may be considered as a palliative or bridging procedure in patients deteriorating despite maximal medical therapy 1, 2.

Critical Care Management

ICU hospitalization is recommended for PH patients with high heart rate (>110 bpm), low blood pressure (systolic <90 mmHg), low urine output, or rising lactate levels 1, 2. Inotropic support is recommended for hypotensive patients 1, 2.

Critical Pitfalls to Avoid

• Never start PAH-specific therapy without right heart catheterization confirmation 2
• Avoid ACE inhibitors, ARBs, and beta-blockers in PAH unless specifically required for comorbidities 2
• Do not use PAH therapies in Group 2 or Group 3 PH 1, 2
• All patients must be evaluated at an expert PH center with multidisciplinary team expertise 1, 3