What is the approach to treating a patient with pulmonary arterial hypertension (PAH)?

Approach to Patient with Pulmonary Arterial Hypertension

Initial Diagnostic Confirmation and Risk Assessment

All patients with suspected PAH must undergo right heart catheterization with acute vasoreactivity testing to guide treatment selection. 1 A positive vasoreactivity response is defined as a fall in mean pulmonary artery pressure ≥10 mmHg to ≤40 mmHg with increased or unchanged cardiac output. 1

• Risk stratification should assess WHO functional class, 6-minute walk distance, BNP/NT-proBNP levels, echocardiographic evidence of right ventricular dysfunction, and hemodynamic parameters. 2
• Patients should be managed at specialized pulmonary hypertension centers with multidisciplinary expertise. 1, 2

Treatment Algorithm by Vasoreactivity and Functional Class

For Vasoreactive Patients (~10% of idiopathic PAH)

High-dose calcium channel blockers are the first-line treatment for the small subset of patients demonstrating acute vasoreactivity. 1, 2

• Use long-acting nifedipine (120-240 mg daily), diltiazem (240-720 mg daily), or amlodipine (up to 20 mg daily). 2, 3
• Avoid verapamil due to negative inotropic effects. 2
• Reassess after 3-6 months; if patients do not achieve WHO functional class I or II, add PAH-specific therapy. 2
• This approach applies primarily to idiopathic PAH and PAH associated with anorexigen use; other PAH etiologies rarely respond to calcium channel blockers long-term. 1

For Non-Vasoreactive Patients: WHO Functional Class II-III

Initial oral combination therapy with ambrisentan plus tadalafil is the recommended first-line treatment, as it has proven superior to monotherapy in delaying clinical failure. 2, 4

• This combination targets two distinct pathways: endothelin receptor antagonism and phosphodiesterase-5 inhibition. 2
• If combination therapy is not tolerated, monotherapy options include:
  • Endothelin receptor antagonists: bosentan (125 mg twice daily) 1, 5 or ambrisentan 1
  • PDE5 inhibitors: sildenafil or tadalafil 1
  • Soluble guanylate cyclase stimulator: riociguat 1

For Non-Vasoreactive Patients: WHO Functional Class IV (High-Risk)

Continuous intravenous epoprostenol is the mandatory first-line therapy for WHO functional class IV patients, as it is the only treatment proven to reduce mortality in high-risk PAH. 2, 3

• IV epoprostenol has demonstrated a reduction in 3-month mortality in high-risk patients. 2
• Alternative parenteral prostanoids include IV treprostinil 6 or subcutaneous treprostinil, though these lack the mortality benefit data of epoprostenol. 1
• Initial combination therapy including IV prostacyclin analogues with oral agents is recommended for high-risk patients. 2

Essential Supportive Measures

All PAH patients require the following supportive care regardless of functional class:

• Diuretics for signs of right ventricular failure and fluid retention. 2, 4
• Supplemental oxygen to maintain arterial oxygen saturation >90% (>91% during air travel or altitude exposure). 1, 2
• Oral anticoagulation (INR 1.5-2.5) should be considered for idiopathic PAH, heritable PAH, and anorexigen-associated PAH. 1, 4
• Immunizations against influenza and pneumococcal pneumonia. 1, 2
• Supervised exercise rehabilitation for physically deconditioned patients. 2

Sequential Treatment Escalation

Reassess patients every 3-6 months using WHO functional class, 6-minute walk distance, and BNP/NT-proBNP levels. 4, 3

Treatment goals include achieving WHO functional class I-II and 6-minute walk distance >440 meters. 2

Adding Therapy for Inadequate Response

If patients remain symptomatic on dual therapy:

• Add inhaled treprostinil to improve 6-minute walk distance in patients on stable doses of an ERA or PDE5 inhibitor. 1
• Add riociguat (soluble guanylate cyclase stimulator) to patients on bosentan, ambrisentan, or inhaled prostanoid. 1
• Add macitentan to patients on PDE5 inhibitor or inhaled prostanoid. 1
• For WHO functional class III-IV patients with deteriorating status despite two drug classes, add a third class of PAH therapy. 1

Critical contraindication: Never combine riociguat with PDE5 inhibitors (sildenafil, tadalafil) due to risk of severe hypotension. 2

Special Populations and Situations

Pregnancy

• Pregnancy must be avoided in all PAH patients due to 30-50% maternal mortality risk. 1
• Estrogen-containing contraceptives are contraindicated due to VTE risk. 1
• Bosentan, ambrisentan, macitentan, and riociguat are pregnancy category X; dual mechanical barrier contraception is mandatory. 1
• If pregnancy occurs, immediate referral to a pulmonary hypertension center with high-risk obstetrics and cardiovascular anesthesiology is essential. 1

Surgery

• Avoid non-essential surgery; when necessary, perform at a pulmonary hypertension center with multidisciplinary perioperative management. 1
• Careful monitoring of clinical status, oxygenation, and hemodynamics postoperatively is critical. 1

Altitude and Air Travel

• Avoid high altitude exposure; use supplemental oxygen during air travel to maintain oxygen saturation >91%. 1
• Patients with borderline oxygen saturations at sea level may require 3-4 L/min supplemental oxygen at altitude or during commercial flights. 1

Transition from Epoprostenol to Treprostinil

• Initiate treprostinil at 10% of current epoprostenol dose and gradually escalate while simultaneously reducing epoprostenol. 6
• Transition must occur in hospital with constant monitoring of walk distance and symptoms. 6
• Treat worsening PAH symptoms with increased treprostinil; treat prostacyclin side effects with decreased epoprostenol. 6

Advanced Therapies for Refractory Disease

Lung transplantation should be considered early after inadequate clinical response on maximal medical therapy. 2, 4

• Indicators for transplant evaluation include WHO functional class III-IV despite maximal therapy, rapidly progressive disease, and hemodynamic deterioration. 4
• Balloon atrial septostomy may be considered as a palliative or bridging procedure to transplantation in patients deteriorating despite maximal medical therapy. 2, 4

Critical Pitfalls to Avoid

• Never abruptly withdraw or suddenly reduce prostacyclin therapy, as this causes acute worsening of PAH and potential death. 6
• Do not use PAH-specific therapies for Group 2 (left heart disease) or Group 3 (lung disease) pulmonary hypertension, as they have not demonstrated benefit and may cause harm. 1, 2
• Titrate slowly in patients with hepatic or renal insufficiency due to increased systemic drug exposure. 6
• Monitor for catheter-related bloodstream infections with IV prostacyclin therapy; subcutaneous administration is preferred when feasible. 6
• Recognize that chronic IV infusions carry approximately 1 bloodstream infection per 3-5 years of use, making infection prevention protocols essential. 6