Is there a role for endothelin (ET) receptor blockers in treating severe pulmonary hypertension secondary to atrial septal defect (ASD)?

Endothelin Receptor Antagonists in Severe Pulmonary Hypertension Secondary to ASD

Endothelin receptor antagonists are generally NOT recommended for severe pulmonary hypertension secondary to atrial septal defect, as the primary treatment strategy should focus on ASD closure when feasible, with targeted PAH therapy reserved only for highly selected cases where shunt closure is contraindicated or to facilitate operability. 1

Primary Treatment Approach

The fundamental management of PAH associated with ASD differs critically from idiopathic PAH:

• ASD closure (surgical or percutaneous) is the definitive treatment when pulmonary vascular resistance remains suitable, as correcting the underlying anatomical defect addresses the root cause 1
• Patients with congenital heart disease-associated PAH, including ASD, have a very low rate of long-term responsiveness to calcium channel blockers compared to idiopathic PAH, and this principle extends to the overall treatment paradigm 1
• The presence of severe PAH does not automatically preclude shunt closure if the hemodynamics are appropriate (typically PVR <4-5 Wood units and Qp:Qs >1.5) 1

Limited Role for Endothelin Receptor Antagonists

ERAs may have a narrow therapeutic window in ASD-related PAH under specific circumstances:

Bridge to Operability Strategy

• In highly selected patients deemed inoperable due to severe irreversible PH, a trial of ERA therapy (specifically bosentan) may reduce pulmonary vascular resistance sufficiently to make them eligible for ASD closure 1
• Case reports demonstrate that 6 weeks to 3 months of bosentan therapy decreased PVR in patients initially considered inoperable, subsequently allowing successful defect closure 1, 2
• This approach requires careful hemodynamic reassessment with right heart catheterization after the ERA trial to confirm improved operability 1, 2

Contraindications to Shunt Closure

• For patients with truly irreversible severe PAH (markedly elevated PVR with normal pulmonary artery wedge pressure) where ASD closure is definitively contraindicated, a trial of either a prostacyclin agonist or an endothelin receptor antagonist may be considered 1
• This represents a weak recommendation with very low-quality evidence, as these patients have fundamentally different pathophysiology than idiopathic PAH 1

Critical Pitfalls to Avoid

Do not initiate ERA therapy without first:

• Performing comprehensive hemodynamic assessment via right heart catheterization to determine operability for ASD closure 1
• Calculating pulmonary vascular resistance and pulmonary-to-systemic flow ratio (Qp:Qs) to assess reversibility 1
• Consulting with congenital heart disease specialists and cardiac surgeons regarding closure feasibility 1

Do not use ERAs as first-line therapy in ASD-related PAH when the defect is amenable to closure, as this delays definitive treatment and may worsen outcomes 1

Monitoring Requirements if ERA Therapy is Initiated

If bosentan or ambrisentan is used in this context:

• Monthly liver function testing is mandatory for bosentan due to 10% risk of aminotransferase elevations >3× upper limit of normal 3, 4
• Pregnancy testing and effective contraception are required, as all ERAs are teratogenic 3, 4
• Hemoglobin/hematocrit monitoring for anemia, particularly with bosentan 3
• Repeat right heart catheterization after 3-6 months to assess hemodynamic response and reassess operability 1, 2

Evidence Quality Considerations

The evidence supporting ERA use in ASD-related PAH is substantially weaker than for idiopathic PAH:

• No randomized controlled trials specifically evaluate ERAs in ASD-associated PAH 1
• Available data consists primarily of case reports and small case series 1, 2
• The 2009 ACCF/AHA consensus document explicitly notes that patients with PAH due to conditions other than idiopathic PAH have very low rates of response to targeted therapies 1
• The mechanism of PAH in ASD (volume overload and increased pulmonary blood flow leading to vascular remodeling) differs fundamentally from idiopathic PAH, making extrapolation of treatment efficacy problematic 1