What is the recommended pharmacologic regimen for an adult with confirmed pulmonary arterial hypertension (PAH) (idiopathic, heritable, drug‑induced, or associated with connective‑tissue disease, HIV, portal hypertension, congenital heart disease) after excluding left‑heart disease or lung disease?

Pharmacotherapy of Pulmonary Arterial Hypertension

All patients with confirmed PAH should be evaluated at an expert center and undergo acute vasoreactivity testing to determine if they are candidates for calcium channel blocker therapy, which is the preferred first-line treatment for the small subset of vasoreactive patients. 1

Initial Assessment and Risk Stratification

Before initiating therapy, systematically evaluate disease severity using WHO functional class, 6-minute walk distance, echocardiographic parameters, hemodynamic variables (right atrial pressure, mean pulmonary artery pressure, cardiac index, pulmonary vascular resistance), and biomarkers like N-terminal pro-BNP 1, 2. This multi-parameter assessment guides all subsequent treatment decisions and should be repeated regularly to assess response.

Refer all patients to a specialized PAH center prior to initiating therapy whenever possible 1, 2. The rarity and complexity of PAH makes accurate diagnosis and optimal drug selection challenging for non-specialists. Ongoing care should involve close collaboration between local physicians and PAH experts 1.

Aggressively treat contributing conditions that worsen pulmonary hypertension, including obstructive sleep apnea, systemic hypertension, and hypoxemia 1. Consider anticoagulation for patients with idiopathic PAH 2.

Vasoreactivity Testing and Calcium Channel Blockers

Perform acute vasoreactivity testing with a short-acting agent (inhaled nitric oxide, IV epoprostenol, or adenosine) during right heart catheterization in all patients without contraindications 1. Contraindications include low systemic blood pressure, low cardiac output, or WHO functional class IV symptoms 1.

A positive vasoreactivity response is defined as a decrease in mean pulmonary artery pressure ≥10 mm Hg to an absolute value <40 mm Hg with unchanged or increased cardiac output 1. Only approximately 10% of idiopathic PAH patients meet these criteria 1.

For vasoreactive patients, initiate high-dose calcium channel blockers (amlodipine, diltiazem, or nifedipine) as first-line therapy 2. These patients have demonstrated 5-18 year survival benefit with CCB therapy 1. Reassess after 3-6 months; if inadequate response, transition to PAH-specific therapies.

Treatment for Non-Vasoreactive Patients

WHO Functional Class I (Asymptomatic)

Monitor asymptomatic patients every 3-6 months without initiating pharmacotherapy 1. No PAH-specific therapy is approved for WHO FC I, and evidence for benefit is lacking. Ensure careful history-taking to confirm true absence of symptoms rather than activity modification.

WHO Functional Class II-III (Symptomatic, Treatment-Naive)

For treatment-naive patients with WHO FC II-III symptoms, initiate combination therapy targeting multiple pathways rather than monotherapy 3. Current evidence demonstrates that combination therapy improves morbidity and mortality compared to single-pathway monotherapy, with 5-year survival exceeding 60% 3.

Preferred initial combination regimens include:

• Phosphodiesterase-5 inhibitor (sildenafil or tadalafil) PLUS endothelin receptor antagonist (ambrisentan or macitentan) 2, 3. This dual-pathway approach has demonstrated superior outcomes in clinical trials.

• Alternative: Soluble guanylate cyclase stimulator (riociguat) as monotherapy or in combination with endothelin receptor antagonists or prostanoids 1, 4. Riociguat improved 6-minute walk distance by 36 meters and reduced pulmonary vascular resistance by 223 dyn/s/cm⁵ compared to placebo 1. Do not combine riociguat with PDE5 inhibitors 1.

Specific dosing:

• Ambrisentan: Start 5 mg once daily, titrate to 10 mg at 4-week intervals as tolerated 5
• Sildenafil: Standard dosing per FDA approval
• Riociguat: Individually titrate up to 2.5 mg three times daily based on blood pressure tolerance 1

WHO Functional Class III-IV (Severe, or Inadequate Response to Initial Therapy)

For patients remaining symptomatic on dual oral therapy, add prostacyclin pathway therapy 4, 2:

• Inhaled treprostinil: Add to existing endothelin receptor antagonist or PDE5 inhibitor therapy 4. Titrate up to 9 inhalations (54 mcg) every 6 hours as tolerated 4. This improved 6-minute walk distance by median 16 meters in clinical trials 1.

• Oral selexipag (prostacyclin receptor agonist): Start 200 mcg twice daily, increase weekly by 200 mcg increments to maximum tolerated dose up to 1,600 mcg twice daily 4, 6. Take with food to improve tolerability 6. This first-in-class oral prostacyclin pathway agent delays disease progression and reduces PAH hospitalizations 4, 6.

• Subcutaneous or IV treprostinil: For more severe patients, demonstrated dose-dependent improvements in hemodynamics including decreased mean pulmonary artery pressure (22.3 mm Hg vs 10.7 mm Hg placebo) and increased cardiac index 1.

For WHO FC IV patients or those with rapidly progressive disease, initiate continuous IV epoprostenol 7. Start at 2 ng/kg/min and increase by 2 ng/kg/min increments every 15 minutes until tolerance limit or clinical benefit is achieved 7. Mean doses in clinical trials reached 11.2 ng/kg/min by week 12 7. IV epoprostenol remains the gold standard for the most severe patients despite requiring continuous infusion through a central venous catheter 7, 3.

Critical Prescribing Considerations

All PAH-specific therapies are pregnancy category X and absolutely contraindicated in pregnancy 4, 5. For females of reproductive potential, exclude pregnancy before starting treatment, monthly during treatment, and one month after discontinuation 5. Ambrisentan is only available through a REMS program due to teratogenicity risk 5.

Avoid abrupt withdrawal or sudden large dose reductions of prostacyclin therapy, which can precipitate clinical deterioration 7. Adjust doses gradually under physician supervision except in life-threatening situations 7.

Dose adjustments for hepatic impairment:

• Selexipag: Reduce to once-daily dosing in moderate hepatic impairment (Child-Pugh B); avoid in severe impairment (Child-Pugh C) 6
• Ambrisentan: Not recommended in moderate-severe hepatic impairment 5

Drug interactions:

• Selexipag: Contraindicated with strong CYP2C8 inhibitors (gemfibrozil); reduce to once-daily with moderate CYP2C8 inhibitors (clopidogrel, deferasirox) 6
• Ambrisentan: Limit to 5 mg daily when co-administered with cyclosporine 5

Monitoring and Treatment Escalation

Reassess patients several hours after each dose adjustment to monitor blood pressure, heart rate, and tolerance 7. Common dose-limiting adverse effects include nausea, vomiting, hypotension, headache, jaw pain, diarrhea, and flushing 1.

Escalate therapy if symptoms persist, recur, or worsen despite current treatment 1, 7. Increase doses gradually at intervals of 24-48 hours or longer, allowing adequate time to assess clinical response 7. The goal is to achieve and maintain clinical stability across multiple parameters (functional class, exercise capacity, hemodynamics, biomarkers) 1, 2.

Monitor hemoglobin at baseline, one month, and periodically thereafter, as decreases occur with endothelin receptor antagonists 5.

Common Pitfalls

Do not use PAH-specific therapies in patients with pulmonary hypertension due to left heart disease or lung disease 8. These patients should have their underlying condition treated; PAH-specific drugs lack evidence of benefit and may cause harm.

If acute pulmonary edema develops during PAH therapy initiation, consider pulmonary veno-occlusive disease and discontinue treatment 5. This represents a distinct pathophysiology requiring different management.

Do not split, crush, or chew tablets of ambrisentan or selexipag 5, 6.