Treatment of Pulmonary Arterial Hypertension
Initial Evaluation and Risk Stratification
All patients with confirmed PAH must be evaluated at an expert PAH center before initiating therapy, using a systematic combination of WHO functional class, 6-minute walk distance, BNP/NT-proBNP levels, echocardiographic parameters (right atrial size, pericardial effusion, TAPSE), and hemodynamic variables (right atrial pressure, cardiac index, pulmonary vascular resistance) to guide all treatment decisions. 1, 2
Right-heart catheterization is mandatory to confirm PAH (mean PAP >20 mmHg, PCWP ≤15 mmHg, PVR ≥3 Wood units) and must include acute vasoreactivity testing with inhaled nitric oxide, IV epoprostenol, or adenosine to identify the ~10% of patients eligible for calcium channel blocker therapy. 1, 2, 3
A positive vasoreactivity response requires a fall in mean PAP of ≥10 mmHg to an absolute value <40 mmHg with stable or increased cardiac output. 1, 2, 3
Follow-up assessments should occur every 3-6 months in stable patients, evaluating WHO functional class, 6-minute walk distance (target >440-500 m), BNP/NT-proBNP (target <50 ng/L), and echocardiography. 1
Treatment Algorithm by WHO Functional Class and Vasoreactivity
Vasoreactive Patients (~10% of idiopathic PAH)
High-dose calcium channel blockers are first-line therapy for vasoreactive patients: long-acting nifedipine 120-240 mg daily, diltiazem 240-720 mg daily, or amlodipine up to 20 mg daily. 1, 2
These patients demonstrate 5-18 year survival benefit with CCB therapy alone. 2
If patients deteriorate on CCB therapy or fail to achieve sustained response, transition to PAH-specific combination therapy. 1, 2
Non-Vasoreactive Patients: WHO Functional Class I (Asymptomatic)
Asymptomatic patients should be monitored every 3-6 months without initiating PAH-specific pharmacotherapy, as no approved therapy has demonstrated benefit in this population. 1, 2
Non-Vasoreactive Patients: WHO Functional Class II-III (Low to Intermediate Risk)
Initial oral combination therapy with ambrisentan plus tadalafil is recommended as first-line treatment for WHO FC II-III patients, as this regimen delays clinical failure and improves outcomes compared to monotherapy. 1, 2, 4
This combination targets two distinct pathways: endothelin receptor antagonism (ambrisentan) and phosphodiesterase-5 inhibition (tadalafil). 2, 4
Alternative oral monotherapy options (if combination is not tolerated) include endothelin receptor antagonists (bosentan, macitentan, ambrisentan), phosphodiesterase-5 inhibitors (sildenafil, tadalafil), or riociguat (soluble guanylate cyclase stimulator). 1, 2, 4
Riociguat is contraindicated when combined with PDE-5 inhibitors. 1, 2
For WHO FC II patients specifically, sildenafil is the preferred oral monotherapy due to ease of administration and favorable side-effect profile. 1
Non-Vasoreactive Patients: WHO Functional Class III (High Risk) or Functional Class IV
For high-risk WHO FC III or FC IV patients, initial combination therapy including intravenous epoprostenol should be prioritized, as it is the only therapy proven to reduce 3-month mortality in high-risk PAH patients. 1, 2
IV epoprostenol is the treatment of choice for WHO FC IV patients and has demonstrated the greatest survival advantage in prospective randomized trials. 1, 2
Alternative prostacyclin options for severe disease include IV treprostinil, subcutaneous treprostinil, or inhaled iloprost, though these have less robust mortality data. 1, 5, 6
Endothelin receptor antagonists (bosentan) and sildenafil are alternative options for WHO FC III-IV patients but are less effective than IV prostacyclin therapy. 1
Sequential Combination Therapy for Inadequate Response
If patients remain symptomatic or deteriorate on initial monotherapy or dual oral therapy, escalate to sequential double or triple combination therapy targeting multiple pathways. 1, 2, 7
Add a prostacyclin-pathway agent (inhaled treprostinil, subcutaneous treprostinil, or IV prostacyclin) to existing oral therapy. 1, 2, 5
Inhaled treprostinil added to an ERA or PDE-5 inhibitor improves 6-minute walk distance by ~16 meters. 2
Subcutaneous or IV treprostinil provides dose-dependent hemodynamic benefits, reducing mean PAP by ~22 mmHg versus ~11 mmHg with placebo. 2
Triple combination therapy should be attempted if patients fail to achieve low-risk status on dual therapy. 1, 2, 7
Essential Supportive Measures
Diuretics and Oxygen
Loop diuretics are indicated for all PAH patients with signs of right ventricular failure and fluid retention (peripheral edema, elevated jugular venous pressure, ascites). 1, 2
Continuous long-term oxygen therapy is indicated when arterial oxygen tension is consistently <60 mmHg (8 kPa) to maintain saturations >90%. 1, 2
In-flight oxygen should be administered to WHO FC III-IV patients and those with arterial oxygen <60 mmHg. 1
Anticoagulation
Oral anticoagulation (target INR 1.5-2.5 in North America, 2.0-3.0 in Europe) should be considered for idiopathic PAH, heritable PAH, and anorexigen-induced PAH. 1, 2
Anticoagulation may be considered for associated PAH (e.g., connective tissue disease, congenital heart disease), though evidence is weaker. 1
General Measures
Pregnancy must be avoided in all PAH patients due to 30-50% maternal mortality; if pregnancy occurs, management should be at a specialized PAH center. 1, 2
Immunization against influenza and pneumococcal infection is recommended. 1, 2
Supervised exercise rehabilitation should be considered for physically deconditioned patients, as it improves exercise capacity and quality of life. 1, 2
Excessive physical activity that leads to distressing symptoms should be avoided. 1
Epidural anesthesia is preferred over general anesthesia for elective surgery when feasible. 1, 2
Psychosocial support is essential given the substantial emotional and financial burden of PAH. 1, 2
Monitoring and Treatment Goals
The primary therapeutic goal is to achieve and maintain low-risk status: WHO FC I-II, 6-minute walk distance >440-500 m, normal or near-normal BNP/NT-proBNP, no pericardial effusion, right atrial pressure <8 mmHg, and cardiac index >2.5 L/min/m². 1, 2
Intermediate-risk status is inadequate and should trigger treatment escalation. 1, 2
Patients should be reassessed at baseline, every 3-6 months, with initiation or changes in therapy, and in case of clinical worsening. 1
Right-heart catheterization should be repeated at initiation or changes in therapy and in case of clinical worsening. 1
Referral for Lung Transplantation
Eligibility for lung transplantation should be considered after inadequate clinical response to initial monotherapy or combination therapy, with referral 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 Pitfalls to Avoid
Do not delay referral to a specialized PAH center—accurate diagnosis and optimal drug selection require expertise that is not widely available. 1, 2
Do not combine riociguat with PDE-5 inhibitors—this combination is contraindicated due to safety concerns. 1, 2
Do not rely on monotherapy for most patients—current evidence strongly supports initial combination therapy targeting multiple pathways. 1, 2, 4, 7
Do not use CCBs in non-vasoreactive patients—they can cause severe side effects including hypotension and right heart failure. 1, 2
Do not delay escalation to IV prostacyclin therapy in high-risk or rapidly deteriorating patients—early initiation improves survival. 1, 2, 5