What is the preferred endothelin receptor antagonist for an adult patient with pulmonary arterial hypertension (PAH)?

Choice of Endothelin Receptor Antagonist in Adults with PAH

For treatment-naive adults with WHO Functional Class II-III pulmonary arterial hypertension, ambrisentan is the preferred endothelin receptor antagonist due to its superior safety profile, once-daily dosing convenience, and lower hepatotoxicity risk compared to bosentan. 1

Initial Monotherapy Selection

Ambrisentan should be initiated at 5 mg once daily and titrated to 10 mg as needed and tolerated at 4-week intervals. 2 This selective ETA receptor antagonist is FDA-approved for WHO Functional Class II-III PAH patients to improve exercise ability and delay clinical worsening. 2

Key Advantages of Ambrisentan:

• Once-daily dosing improves adherence compared to twice-daily bosentan 1
• Lower hepatotoxicity risk requires less intensive monitoring than bosentan's mandatory monthly liver function tests 3, 1
• Selective ETA antagonism preserves ETB receptor-mediated vasodilation and endothelin clearance 4, 2
• Established efficacy in idiopathic/heritable PAH (60%) and connective tissue disease-associated PAH (34%) 2

When to Consider Bosentan Instead

Bosentan (dual ETA/ETB antagonist) remains an appropriate alternative in specific scenarios:

• WHO Functional Class III patients where bosentan has Grade A evidence for improving exercise capacity, functional class, and hemodynamics 3, 1
• Patients requiring twice-daily dosing for medication adherence reasons 3
• When ambrisentan is contraindicated or not tolerated 1

Bosentan dosing: Start 62.5 mg twice daily for 4 weeks, then increase to 125 mg twice daily if well tolerated. 3, 1

Critical Monitoring Requirements

For Ambrisentan:

• Pregnancy testing: Required at baseline, monthly during treatment, and 1 month after discontinuation 2
• Hemoglobin/hematocrit: At initiation, 1 month, then periodically 2
• Liver function tests: Less frequent than bosentan, but monitor if clinically indicated 3

For Bosentan:

• Monthly liver function tests are mandatory due to 10-11% risk of aminotransferase elevation >3× upper limit of normal 3, 1
• Monthly pregnancy testing in women of childbearing age 1
• Regular hemoglobin monitoring for anemia 3, 1

Functional Class-Specific Approach

WHO Functional Class II-III (Treatment-Naive):

Initiate ambrisentan 5 mg once daily as first-line monotherapy. 1, 2 This represents the optimal balance of efficacy, safety, and convenience for most patients.

WHO Functional Class III (Alternative):

Bosentan 62.5 mg twice daily (titrate to 125 mg twice daily) is an acceptable alternative with Grade A evidence. 3, 1

WHO Functional Class IV:

IV epoprostenol remains the treatment of choice. 3 Bosentan has only Grade B recommendation for this population. 3 For FC IV patients unable or unwilling to use parenteral prostanoids, consider inhaled prostanoid combined with oral PDE5 inhibitor and ERA. 4

Combination Therapy Considerations

When patients remain symptomatic on stable ERA monotherapy:

• Add inhaled treprostinil to improve 6-minute walk distance 4
• Add PDE5 inhibitor (sildenafil or tadalafil) for improved exercise capacity 4, 1
• Add riociguat (soluble guanylate cyclase stimulator) to improve functional class and delay clinical worsening 4
• Consider macitentan for patients on PDE5 inhibitor or inhaled prostanoid to delay time to clinical worsening 4, 1

Critical Safety Warnings

Absolute Contraindications for All ERAs:

• Pregnancy: All ERAs are teratogenic and contraindicated. 3, 2 Effective contraception is mandatory during treatment and for 1 month after discontinuation.
• Idiopathic pulmonary fibrosis: ERAs are contraindicated and may cause harm. 3, 2

Important Drug Interactions:

• Cyclosporine with ambrisentan: Limit ambrisentan dose to 5 mg once daily 2
• Hormonal contraceptives with bosentan: Bosentan induces CYP3A4/CYP2C9, potentially decreasing contraceptive efficacy; use additional barrier methods 1

Common Pitfalls to Avoid

1. Never initiate bosentan simultaneously with IV epoprostenol in patients starting prostacyclin therapy 4, 1
2. Never start ERAs without baseline liver function tests 3, 1
3. Never use ERAs in pulmonary hypertension due to lung disease (e.g., COPD) as they provide no benefit and may cause harm 5
4. Never fail to confirm pregnancy status before initiating therapy in women of childbearing potential 3, 2
5. Never discontinue monthly monitoring for bosentan patients, as hepatotoxicity can develop at any time 1

Transitioning Between ERAs

Patients can safely transition from one ERA to another (e.g., ambrisentan to bosentan or vice versa) without hemodynamic or hematologic deterioration when there is inadequate response, development of side effects, or need for different dosing schedule. 3

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