What is the recommended approach to diagnose and manage pulmonary arterial hypertension, including risk stratification, supportive care, and pharmacologic therapy?

Management of Pulmonary Arterial Hypertension

Right heart catheterization is mandatory before initiating any PAH-specific therapy to confirm the diagnosis, establish hemodynamic classification, and guide treatment decisions. 1, 2, 3

Diagnostic Confirmation and Classification

Perform right heart catheterization to confirm pulmonary hypertension (mean PAP > 20 mmHg) and specifically diagnose PAH (Group 1) by demonstrating mean PAP > 20 mmHg, pulmonary artery wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance > 3 Wood units. 4, 3, 5

Critical pitfall: Do not start PAH-specific drugs without catheterization-confirmed Group 1 PAH, as these medications can be harmful in left heart disease (Group 2) pulmonary hypertension. 4, 6

Essential Diagnostic Workup

• Echocardiography serves as the initial screening test, looking for elevated tricuspid regurgitant velocity, right ventricular enlargement, and reduced TAPSE. 3
• Ventilation-perfusion scanning must be performed to exclude chronic thromboembolic pulmonary hypertension (CTEPH); a normal scan effectively rules out CTEPH. 1, 3
• Laboratory testing including HIV serology, connective tissue disease markers (ANA, anti-Scl-70, anti-centromere), thyroid function, and liver function tests to identify associated conditions. 3
• High-resolution chest CT to evaluate for interstitial lung disease, emphysema, or pulmonary veno-occlusive disease. 3

Risk Stratification

Assess risk at baseline and every 3-6 months using a multiparametric approach that includes WHO functional class, 6-minute walk distance, BNP/NT-proBNP levels, echocardiographic parameters (right atrial size, pericardial effusion, TAPSE), and hemodynamic measurements (right atrial pressure, cardiac index). 1, 2, 7

Low-risk criteria include WHO functional class I-II, 6-minute walk distance > 440 meters (>500 meters optimal), BNP < 50 ng/L or NT-proBNP < 300 ng/L, no pericardial effusion, TAPSE > 20 mm, right atrial pressure < 8 mmHg, and cardiac index > 2.5 L/min/m². 4, 3

Initial Pharmacologic Therapy

Vasoreactivity Testing (Only for Idiopathic, Heritable, and Drug-Induced PAH)

Perform acute vasoreactivity testing during right heart catheterization using short-acting agents (IV epoprostenol, adenosine, or inhaled nitric oxide) in patients with idiopathic, heritable, or drug-induced PAH. 1, 2

Do not perform vasoreactivity testing in connective tissue disease-associated PAH, congenital heart disease-associated PAH, HIV-associated PAH, portopulmonary hypertension, or any Group 2-5 pulmonary hypertension. 4

Positive vasoreactivity is defined as a fall in mean PAP of at least 10 mmHg to ≤ 40 mmHg with increased or unchanged cardiac output. 1, 2

For Vasoreactive Patients (~10% of Idiopathic PAH)

Initiate high-dose calcium channel blockers as first-line therapy: long-acting nifedipine 120-240 mg daily, diltiazem 240-720 mg daily, or amlodipine up to 20 mg daily. 4, 2

Critical safety warning: Never start calcium channel blockers without documented positive vasoreactivity testing, as this can cause life-threatening hypotension and right ventricular ischemia. 4

Mandatory reassessment: Repeat right heart catheterization at 3-4 months after initiating calcium channel blocker therapy. If the patient is not in WHO functional class I-II with marked hemodynamic improvement, add PAH-specific combination therapy. 4, 2

For Non-Vasoreactive Patients

Low or Intermediate Risk Patients

Initiate oral combination therapy with ambrisentan plus tadalafil as first-line treatment, which has demonstrated superiority over monotherapy in delaying clinical failure. 4, 2

Alternative initial oral combination therapy includes an endothelin receptor antagonist (bosentan, ambrisentan, or macitentan) plus a phosphodiesterase-5 inhibitor (sildenafil or tadalafil). 1, 3

High-Risk Patients

Initiate combination therapy that includes intravenous prostacyclin analogue (preferably IV epoprostenol) because it reduces 3-month mortality in high-risk patients. 4, 2

Sequential Escalation for Inadequate Response

Escalate to double or triple combination therapy if the initial regimen fails to achieve low-risk status at 3-6 month follow-up. 4, 2

Contraindication: Do not combine riociguat with a phosphodiesterase-5 inhibitor due to safety concerns. 4

Supportive Care (All PAH Patients)

Mandatory Interventions

• Diuretics (typically furosemide) are indicated for all patients with signs of right ventricular failure and fluid retention, with monitoring of electrolytes and renal function. 1, 4, 3
• Continuous long-term supplemental oxygen when arterial oxygen pressure is consistently < 60 mmHg (8 kPa) or to maintain saturations > 90%. 1, 4, 3
• Pregnancy avoidance is absolutely contraindicated due to 30-50% maternal mortality risk. 1, 4
• Immunization against influenza and pneumococcal infection. 1, 4

Strongly Recommended Interventions

• Oral anticoagulation (target INR 1.5-2.5) should be considered in idiopathic, heritable, and anorexigen-induced PAH. 1, 4
• Supervised exercise rehabilitation for physically deconditioned patients. 1, 4
• Psychosocial support should be considered. 1
• In-flight oxygen administration for WHO functional class III-IV patients and those with arterial oxygen pressure < 60 mmHg. 1

Contraindications

Avoid excessive physical activity that leads to distressing symptoms. 1, 4

Monitoring and Follow-Up

Reassess every 3-6 months in stable patients with the following parameters: 1, 4, 3

• WHO functional class
• 6-minute walk test
• BNP or NT-proBNP levels
• Echocardiography (right ventricular size/function, pericardial effusion, TAPSE)
• ECG
• Cardiopulmonary exercise testing (one of the two exercise tests)

Perform right heart catheterization at baseline, with initiation or changes in therapy, and in cases of clinical worsening. 1

Primary treatment goal: Achieve and maintain low-risk status (WHO functional class I-II with supporting hemodynamic and biomarker parameters). 4, 3, 7

Advanced Therapies

Lung Transplantation

Refer for lung transplantation evaluation after inadequate response to initial monotherapy or combination therapy, and soon after confirming inadequate response on maximal combination therapy. 4, 3

Bilateral lung transplant is the procedure of choice for PAH patients undergoing transplantation. 1

Rescue Interventions

• Balloon atrial septostomy may be considered as a palliative or bridging procedure in patients deteriorating despite maximal medical therapy. 4, 3
• Veno-arterial ECMO can be employed in awake, end-stage patients as a bridge to lung transplantation. 4

Critical Care Management

ICU admission is indicated for hemodynamic instability: heart rate > 110 bpm, systolic blood pressure < 90 mmHg, oliguria, or rising lactate. 4

Provide inotropic support to hypotensive patients. 4

Management of Non-PAH Pulmonary Hypertension

Group 2 (Left Heart Disease)

PAH-specific drugs are not recommended and may be harmful in Group 2 pulmonary hypertension. Management focuses on optimal treatment of the underlying cardiac condition and diuretics for volume control. 1, 4, 6

Group 3 (Lung Disease)

PAH-specific therapies are not recommended. Treatment is directed at the underlying lung pathology and long-term oxygen therapy where appropriate. 4

Group 4 (Chronic Thromboembolic Pulmonary Hypertension)

Surgical pulmonary endarterectomy in deep hypothermia with circulatory arrest is the treatment of choice and should be performed at experienced centers. 1, 4

Operability assessment must be performed by a multidisciplinary expert team including cardiology, respiratory medicine, radiology, and surgical expertise. 1, 4

Group 5 (Multifactorial Mechanisms)

Therapy is directed at the underlying disease; PAH-specific agents are not advised. 4

Important Drug Interactions

Bosentan with cyclosporine: Combination contraindicated due to 4-fold increase in bosentan levels and 50% decrease in cyclosporine levels. 1

Bosentan with glibenclamide: Combination contraindicated due to increased incidence of elevated aminotransferases and potential decrease in hypoglycemic effect. 1

Bosentan with hormonal contraceptives: Hormone levels decrease, making contraception unreliable; alternative contraceptive methods required. 1

Bosentan with warfarin: Intensified INR monitoring recommended following initiation, though dose adjustment usually unnecessary. 1