What is the recommended treatment approach for pulmonary hypertension, including management for each WHO classification group?

Treatment of Pulmonary Hypertension

Treatment of pulmonary hypertension is fundamentally determined by the WHO clinical classification group, with Group 1 pulmonary arterial hypertension (PAH) requiring specific PAH-targeted therapies, while Groups 2-5 should NOT receive PAH-specific drugs as they may cause harm. 1, 2

Mandatory Diagnostic Confirmation Before Any Treatment

• Right heart catheterization (RHC) is absolutely required to confirm the diagnosis and establish hemodynamic classification before initiating any therapy 1, 3, 2
• RHC must document: mean pulmonary artery pressure >20 mmHg, pulmonary artery wedge pressure ≤15 mmHg, and pulmonary vascular resistance >3 Wood units to confirm Group 1 PAH 3
• Ventilation-perfusion (V/Q) scan is mandatory in all patients to exclude chronic thromboembolic PH (Group 4), as it has 90-100% sensitivity 3, 2
• All patients must be evaluated at an expert pulmonary hypertension center before starting treatment 2

Group 1: Pulmonary Arterial Hypertension (PAH) - Specific Treatment Algorithm

Step 1: Vasoreactivity Testing (Only for Select Patients)

Vasoreactivity testing is ONLY performed in idiopathic PAH, heritable PAH, and drug-induced PAH—it is contraindicated and potentially harmful in all other PAH subtypes and all other PH groups. 3, 2

• Eligible patients: idiopathic PAH, heritable PAH, drug-induced PAH 3
• Ineligible patients (Class III contraindication): connective tissue disease-PAH, congenital heart disease-PAH, HIV-PAH, portopulmonary hypertension, pulmonary veno-occlusive disease, and all Groups 2-5 PH 3
• Use inhaled nitric oxide as the preferred vasodilator; alternatives include IV epoprostenol or adenosine 3
• Never use oral or IV calcium channel blockers during acute testing 3

Positive vasoreactivity response requires ALL three criteria:

1. Decrease in mean PAP ≥10 mmHg
2. Absolute mean PAP ≤40 mmHg
3. Cardiac output unchanged or increased 3

• Only 10-15% of idiopathic PAH patients meet positive response criteria 3

Step 2A: Treatment for Vasoreactive Patients (Positive Test)

High-dose calcium channel blockers (CCBs) are first-line therapy ONLY for documented vasoreactive patients. 3, 2

Drug selection based on resting heart rate:

• HR <70-75 bpm: Extended-release nifedipine (target 120-240 mg daily) or amlodipine (up to 20 mg daily) 3
• HR >75-80 bpm: Diltiazem (target 240-720 mg daily) 3

Critical safety requirements:

• Mandatory repeat RHC at 3-4 months to identify non-responders 3
• Approximately 50% of acute responders lose efficacy over time and require escalation to PAH-specific therapy 3
• Never start CCBs without documented positive vasoreactivity testing—this can cause life-threatening hypotension, reflex tachycardia, and right ventricular ischemia 3, 2
• Monitor blood pressure at every dose increase; reduce if systolic <90 mmHg 3

Step 2B: Treatment for Non-Vasoreactive Patients (Negative Test or Not Tested)

Treatment intensity is determined by risk stratification at presentation:

Low or Intermediate Risk Patients:

Initial oral combination therapy with ambrisentan plus tadalafil is recommended as it has proven superior to monotherapy in delaying clinical failure. 1, 2

Alternative approaches for low/intermediate risk 1, 2:

• Initial approved monotherapy (endothelin receptor antagonist, phosphodiesterase-5 inhibitor, or prostacyclin analogue)
• If inadequate response to monotherapy, add sequential combination therapy 1, 2

High Risk Patients:

Initial combination therapy including intravenous prostacyclin analogues should be prioritized, with IV epoprostenol as the preferred agent since it has reduced 3-month mortality in high-risk PAH patients. 1, 2

Step 3: Sequential Escalation for Inadequate Response

• If inadequate clinical response to initial combination therapy or monotherapy, escalate to sequential double or triple combination therapy 1
• The combination of riociguat and PDE-5 inhibitors is contraindicated 1
• Consider eligibility for lung transplantation after inadequate response on maximal combination therapy 1, 2

Group 2: Pulmonary Hypertension Due to Left Heart Disease

PAH-specific therapies are NOT recommended for Group 2 PH and may be harmful. 1, 2

• Treatment focuses on optimizing management of the underlying left heart disease 2, 4
• Diuretics for volume management 2
• No role for endothelin receptor antagonists, PDE-5 inhibitors, or prostacyclins 1, 2

Group 3: Pulmonary Hypertension Due to Lung Disease

PAH-specific therapies are NOT recommended for Group 3 PH. 1, 2

• Long-term oxygen therapy is recommended to maintain saturations >90% and has been shown to partially reduce PH progression 2
• Treatment of the underlying lung disease is the primary approach 4, 5
• PAH drugs may only be considered in highly selected cases with severe PH (mean PAP ≥35 mmHg or mean PAP 25-35 mmHg with cardiac index <2.0 L/min/m²) at expert centers 6

Group 4: Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Surgical pulmonary endarterectomy in deep hypothermia with circulatory arrest is the treatment of choice and should be performed at experienced centers. 1, 2

• Assessment of operability and treatment decisions must be made by a multidisciplinary expert team 1
• For inoperable patients, balloon pulmonary angioplasty or medical therapy with riociguat can be considered 4
• Anticoagulation targeting INR 2-3 is recommended 2

Group 5: Pulmonary Hypertension with Unclear/Multifactorial Mechanisms

• Treatment directed at the underlying causal disease 4, 5
• PAH therapeutics are not recommended 4

Essential Supportive Care for All PAH Patients (Group 1)

General measures that apply to all Group 1 PAH patients:

• Diuretics are recommended for all PAH patients with signs of right ventricular failure and fluid retention 1, 2
• Continuous long-term oxygen when arterial oxygen pressure is consistently <60 mmHg (8 kPa) or to maintain saturations >90% 1, 2
• Anticoagulation should be considered in idiopathic PAH, heritable PAH, and anorexigen-induced PAH, targeting INR 1.5-2.5 1, 2
• Pregnancy is absolutely contraindicated in PAH due to 30-50% mortality risk 1
• Vaccinate against influenza and pneumococcal pneumonia 1
• Avoid altitudes above 1,500-2,000 m without supplemental oxygen 1
• Supervised exercise rehabilitation may be undertaken 1

Monitoring and Treatment Goals

Regular assessments every 3-6 months in stable patients should include: 1, 2, 7

• WHO functional class
• 6-minute walk distance (target >440 meters for most patients) 2
• BNP/NT-proBNP levels (target <50 ng/L) 1, 2
• Echocardiography 2
• Basic biochemistry and hematology 1

The primary treatment goal is achieving and maintaining low-risk status, typically WHO functional class I-II. 2, 7

Better prognostic indicators include 1:

• No clinical evidence of right ventricular failure
• Slow rate of symptom progression
• No syncope
• WHO functional class I-II
• 6-minute walk distance >500 m
• Normal or near-normal BNP/NT-proBNP levels
• No pericardial effusion on echo
• Right atrial pressure <8 mmHg and cardiac index >2.5 L/min/m²

Critical Care and Advanced Interventions

ICU hospitalization is recommended for PH patients with: 1, 2

• Heart rate >110 bpm

• Systolic blood pressure <90 mmHg

• Low urine output

• Rising lactate levels

• Inotropic support is recommended for hypotensive patients 1, 2

• Lung transplantation is recommended soon after inadequate clinical response on maximal medical therapy 1, 2

• Balloon atrial septostomy may be considered as a palliative or bridging procedure after failure of maximal medical therapy 1, 2

• Veno-arterial ECMO may be employed in awake end-stage PH patients for bridging to lung transplantation 1

Critical Pitfalls to Avoid

• Do NOT start PAH-specific drugs without confirming diagnosis and classification via RHC—this can delay appropriate treatment and cause harm, particularly in Group 2 PH 2
• Do NOT perform vasoreactivity testing in connective tissue disease-PAH, congenital heart disease-PAH, HIV-PAH, portopulmonary hypertension, or any Group 2-5 PH—it offers no benefit and adds risk 3
• Do NOT start CCBs without documented positive vasoreactivity testing—fatal outcomes have been reported when CCBs are given to non-vasoreactive patients 3
• Do NOT omit the 3-4 month repeat RHC in patients treated with CCBs—failure to identify non-responders delays necessary therapy escalation 3
• Do NOT use PAH-approved therapies in Group 2 or Group 3 PH outside of clinical trials—they are not recommended and may be harmful 1, 2
• Avoid ACE inhibitors, ARBs, and beta-blockers in PAH unless specifically required for comorbidities, as they lack proven benefit 2