What is the treatment for pulmonary artery hypertension (PAH)?

Treatment of Pulmonary Arterial Hypertension

For treatment-naive PAH patients with WHO Functional Class II-III symptoms, initial combination therapy with ambrisentan and tadalafil is recommended as first-line treatment to improve exercise capacity and delay clinical worsening. 1, 2

Initial Assessment and Vasoreactivity Testing

Before initiating therapy, all patients must undergo acute vasoreactivity testing during right heart catheterization. 1, 3 A positive response is defined as a fall in mean pulmonary artery pressure of at least 10 mm Hg to ≤40 mm Hg with increased or unchanged cardiac output. 1

• Only 5-10% of idiopathic PAH patients demonstrate acute vasoreactivity and are candidates for calcium channel blocker therapy. 1, 2
• Vasoreactivity testing should use short-acting agents like inhaled nitric oxide rather than oral calcium channel blockers, which can cause dangerous hemodynamic deterioration in non-responders due to their long half-life. 1

Treatment Algorithm by WHO Functional Class

WHO Functional Class I-II (Vasoreactive Patients Only)

High-dose calcium channel blockers are the treatment of choice for the small subset of vasoreactive patients. 1, 2

• Use long-acting nifedipine (120-240 mg daily), diltiazem (240-720 mg daily), or amlodipine (up to 20 mg daily). 1
• Avoid verapamil due to negative inotropic effects. 2
• Reassess at 3 months: if the patient has not improved to WHO FC I or II, add PAH-specific therapy immediately. 1
• Important caveat: Even though patients with connective tissue disease-associated PAH may occasionally show vasoreactivity, calcium channel blockers have not proven effective in this population. 1

WHO Functional Class II-III (Non-Vasoreactive or CCB Failures)

Initial combination therapy with ambrisentan and tadalafil is superior to monotherapy and should be the default approach. 1, 2

• This combination has demonstrated superiority in delaying clinical failure compared to monotherapy in randomized trials. 1, 2
• The ambrisentan dose is typically 5-10 mg daily, and tadalafil 20-40 mg daily. 4

For patients unwilling or unable to tolerate combination therapy, monotherapy options include: 1

• Endothelin receptor antagonists: Bosentan (strong recommendation for improving 6-minute walk distance) or ambrisentan. 1
• PDE5 inhibitors: Sildenafil (strong recommendation for improving 6-minute walk distance). 1
• Soluble guanylate cyclase stimulator: Riociguat. 1

Critical consideration: When choosing between oral agents for monotherapy, consider specific toxicities:

• Avoid bosentan in patients with liver abnormalities or inability to undergo monthly liver function monitoring. 1
• Avoid sildenafil in patients with ocular disease or recurrent epistaxis. 1

Parenteral or inhaled prostanoids should NOT be chosen as initial therapy for WHO FC II patients. 1

WHO Functional Class III (Advanced Disease or Inadequate Response)

For patients with more advanced FC III disease or those who fail to meet treatment goals on oral therapy:

Add a parenteral or inhaled prostanoid to existing oral therapy. 1

• Inhaled treprostinil can be added to stable doses of an ERA or PDE5 inhibitor to improve 6-minute walk distance. 1
• Continuous subcutaneous treprostinil is an alternative option. 1
• IV epoprostenol or IV treprostinil should be considered for patients with evidence of clinical deterioration despite oral combination therapy. 1

WHO Functional Class IV

Continuous IV epoprostenol is the treatment of choice for WHO FC IV patients and is the only therapy proven to reduce mortality. 1, 2

• IV epoprostenol has rapid, predictable onset of action and extensive clinical experience supports its use in critically ill patients. 1
• IV treprostinil is an acceptable alternative with accumulating experience. 1, 5
• Start at 1.25 ng/kg/min; if not tolerated due to systemic effects, reduce to 0.625 ng/kg/min. 5
• Titrate upward by 1.25 ng/kg/min per week for the first 4 weeks, then 2.5 ng/kg/min per week thereafter based on clinical response. 5

For FC IV patients who refuse or cannot manage IV therapy: 1

• Consider inhaled prostanoid in combination with an oral PDE5 inhibitor and ERA, though this approach lacks robust evidence. 1
• Oral, subcutaneous, and inhaled agents should generally not be used as first-line monotherapy in FC IV patients. 1

Essential Supportive Therapies

Anticoagulation

Oral anticoagulation with warfarin is recommended for all patients with idiopathic PAH, heritable PAH, and anorexigen-associated PAH. 1, 2

• Target INR 2.0-3.0 (European practice) or 1.5-2.5 (North American practice). 1
• The evidence is based on retrospective single-center studies showing survival benefit. 1
• Exercise caution in specific populations: Patients with connective tissue disease-associated PAH have higher gastrointestinal bleeding risk; patients with congenital heart disease and intracardiac shunts risk hemoptysis but also paradoxical embolism. 1
• Patients on chronic IV epoprostenol should receive anticoagulation due to additional catheter-associated thrombosis risk. 1

Diuretics

Diuretics are indicated for all PAH patients with signs of right ventricular failure and fluid retention. 1, 2, 6

• 49-70% of patients in recent randomized trials were receiving diuretics. 1
• Monitor serum electrolytes and renal function closely. 1

Oxygen Therapy

Supplemental oxygen is recommended to maintain oxygen saturation >90% (or >91% per some guidelines). 1, 3, 2, 6

• Continuous long-term oxygen therapy is indicated when arterial PO2 is consistently <60 mm Hg (8 kPa). 2
• Patients should use supplemental oxygen during air travel to maintain adequate saturations. 3

Additional Supportive Measures

• Immunizations: Influenza and pneumococcal vaccines are recommended. 3, 2
• Exercise rehabilitation: Supervised exercise training should be considered for physically deconditioned patients already on medical therapy. 2
• Pregnancy avoidance: Pregnancy carries 30-50% mortality risk and is contraindicated; if it occurs, care must be provided at specialized centers. 3, 2
• Anemia management: Patients are highly sensitive to reductions in hemoglobin; treat any mild anemia promptly. 1

Monitoring and Follow-Up

Patients should be reassessed every 3 months (or more frequently for advanced disease) with functional class assessment and 6-minute walk test. 1, 2, 6

• Less ill patients on stable oral therapy can be seen every 3-6 months. 1, 6
• Treatment goals include achieving WHO FC I or II and 6-minute walk distance >440 meters. 2
• Risk stratification tools like the REVEAL score can guide therapy escalation decisions. 1

Advanced Therapies

Lung transplantation should be considered for patients with inadequate clinical response to maximal medical therapy. 1, 2, 6

• Referral should occur soon after failure to respond to optimal medical management. 2
• Balloon atrial septostomy may be considered as a palliative or bridging procedure in patients deteriorating despite maximal therapy. 2

Critical Pitfalls to Avoid

• Never abruptly discontinue prostacyclin infusions as this can cause rebound pulmonary hypertension and death. 5
• Do not use calcium channel blockers empirically without documented vasoreactivity as they can cause hemodynamic deterioration in non-responders. 1
• Avoid riociguat in combination with PDE5 inhibitors due to risk of severe hypotension. 2
• Do not use PAH-specific therapies in Group 2 PH (left heart disease) as they can worsen outcomes. 1, 6
• Delayed referral to specialized PH centers results in inappropriate treatment and worse outcomes; all PAH patients should be managed at or in consultation with expert centers. 1, 2, 6