Can Endothelin (ET) antagonists and Phosphodiesterase (PDE) inhibitors be used in patients with secondary Pulmonary Arterial Hypertension (PAH)?

Use of Endothelin Antagonists and Phosphodiesterase Inhibitors in Secondary Pulmonary Arterial Hypertension

Direct Answer

Endothelin antagonists and phosphodiesterase-5 inhibitors should NOT be routinely used in secondary pulmonary hypertension, with the critical exception of PAH associated with connective tissue disease (particularly systemic sclerosis) where these agents are recommended using the same treatment algorithms as idiopathic PAH. 1

Critical Distinction: Secondary PAH vs. Other Forms of Secondary PH

The answer depends entirely on what type of "secondary" pulmonary hypertension you are treating:

Group 1 PAH (Where ERAs and PDE5i ARE Indicated)

These medications are proven effective in:

• PAH associated with systemic sclerosis (SSc-PAH) - the most common and well-studied secondary PAH 1
• PAH associated with congenital heart disease (with specific hemodynamic criteria) 2
• PAH associated with HIV infection, drugs/toxins, or portal hypertension 1

For these conditions, combination oral therapy with an ERA plus PDE5 inhibitor is now first-line treatment for treatment-naive patients at lower or intermediate risk 1. Historically, monotherapy was used, but this approach is now reserved only for very mild PAH (WHO functional class I, pulmonary vascular resistance 3-4 Wood units, mean pulmonary arterial pressure <30 mmHg) 1.

Other Forms of Secondary PH (Where ERAs and PDE5i Are NOT Indicated)

These medications should be avoided in:

• Pulmonary hypertension due to left heart disease (Group 2) - no evidence of benefit 1
• Pulmonary hypertension due to chronic lung disease/hypoxia (Group 3) - not indicated 1
• Chronic thromboembolic pulmonary hypertension (Group 4) - surgical intervention is primary treatment 1

Treatment Algorithm for Secondary PAH (Group 1)

For Systemic Sclerosis-Associated PAH (SSc-PAH)

Initial Risk Stratification Using REVEAL 2.0 Calculator: 1

Lower or Intermediate Risk Patients:

• First-line: Oral combination therapy with ERA + PDE5 inhibitor 1
• Available ERAs: Bosentan (62.5-125mg twice daily), Ambrisentan (5-10mg daily), Macitentan (10mg daily) 1
• Available PDE5 inhibitors: Sildenafil (20mg three times daily), Tadalafil (40mg daily) 1

Monotherapy acceptable only if: 1

• Very mild PAH (WHO functional class I, PVR 3-4 Wood units, mPAP <30 mmHg, normal right ventricle)
• Suspicion of pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis
• Long-term stable monotherapy (>5-10 years) with low-risk profile
• Combination therapy unavailable or contraindicated (e.g., severe liver disease)

High Risk Patients:

• Combination therapy including intravenous prostacyclin analogue 1
• Consider referral for lung transplantation 1

Reassessment at 3-6 Months

If Low Risk Achieved:

• Continue structured follow-up 1

If Intermediate or High Risk:

• Escalate to triple combination therapy (ERA + PDE5 inhibitor + prostacyclin analogue) 1

Special Case: PAH Secondary to Atrial Septal Defect

Primary treatment is ASD closure, NOT medical therapy 2. ERAs and PDE5 inhibitors have an extremely limited role:

• Only consider ERA therapy (bosentan) in highly selected inoperable patients to potentially reduce pulmonary vascular resistance sufficiently to make them eligible for ASD closure 2
• This represents a weak recommendation with very low-quality evidence 2
• Critical pitfall: Never initiate ERA therapy without comprehensive hemodynamic assessment via right heart catheterization to determine operability 2

Evidence Supporting Combination Therapy

Network meta-analysis data (2022) demonstrates: 3

• Bosentan + Sildenafil showed greatest improvement in 6-minute walk distance (WMD=53.93m, 95%CI=6.19-101.66) compared to placebo 3
• Bosentan + Tadalafil (WMD=50.84m) and Ambrisentan + Tadalafil (WMD=46.67m) also significantly improved exercise capacity 3
• Combination therapy showed no significant difference in adverse events compared to monotherapy 3

For clinical worsening prevention: 3

• Bosentan + Tadalafil performed best (OR=0.08,95%CI=0.01-0.49) compared to placebo 3

Mandatory Monitoring Requirements

For All ERAs:

• Monthly liver function tests due to hepatotoxicity risk (10% incidence of aminotransferase elevation >3× normal with bosentan) 4, 2
• Pregnancy testing and effective contraception mandatory - all ERAs are teratogenic 4, 2
• Regular hemoglobin/hematocrit monitoring - ERAs may cause mild anemia 4

For PDE5 Inhibitors:

• Monitor for visual disturbances (transient color discrimination impairment possible at higher doses) 5
• Contraindicated with nitrates due to severe hypotension risk 5

Critical Pitfalls to Avoid

1. Do not extrapolate PAH treatment guidelines to other forms of pulmonary hypertension (Groups 2-5) - the evidence base is specific to Group 1 PAH 1

2. Do not use calcium channel blockers without documented vasoreactivity testing - only 5-10% of idiopathic PAH patients respond, and even fewer with connective tissue disease-associated PAH 2, 6

3. Do not delay referral to a specialized pulmonary hypertension center for risk stratification and treatment optimization 1, 6

4. Do not initiate ERAs without baseline liver function tests 4, 2

5. Do not assume asymptomatic patients do not require treatment - even low-risk patients need therapy to maintain their low-risk state 6

6. Do not use sildenafil chronically in pediatric PAH - increased mortality observed with chronic use in children (hazard ratio 3.5 for high vs. low dose, p=0.015) 5

Drug Interaction Considerations

Sitaxsentan (selective ETA antagonist): 4

• Inhibits CYP2C9, significantly increasing INR/prothrombin time 4
• Requires warfarin dose reduction if co-administered 4
• Associated with fatal hepatitis at higher doses 4

Bosentan: 7

• Induces CYP3A4 and CYP2C9, potentially reducing efficacy of other medications 7