What is the best treatment approach for an adult patient with pulmonary arterial hypertension (PAH) who remains symptomatic on stable endothelin receptor antagonist (ERA) monotherapy, considering the use of macitentan?

Macitentan for Symptomatic PAH on ERA Monotherapy

For adult PAH patients who remain symptomatic on stable endothelin receptor antagonist (ERA) monotherapy, add macitentan if the patient is currently on a PDE5 inhibitor or inhaled prostanoid as background therapy—not if they are on another ERA. 1

Critical Context: When Macitentan Is Appropriate

The CHEST guidelines specifically recommend macitentan for patients symptomatic on PDE5 inhibitor or inhaled prostanoid background therapy, not for those on ERA monotherapy. 1 This is a crucial distinction that prevents inappropriate ERA-on-ERA combinations.

If your patient is truly on ERA monotherapy alone and remains symptomatic, the correct approach is:

Add-On Therapy Options for Symptomatic Patients on ERA Monotherapy

• First-line recommendation: Add inhaled treprostinil to improve 6-minute walk distance (6MWD), with strong evidence supporting this combination 1
• Alternative option: Add inhaled iloprost to improve 6MWD and WHO functional class 1
• Consider adding riociguat (soluble guanylate cyclase stimulator) to improve 6MWD, WHO functional class, and delay time to clinical worsening 1

Dosing Considerations for Add-On Therapies

• Inhaled treprostinil: Start with 3 inhalations (18 μg) every 6 hours, titrate up to 9 inhalations (54 μg) every 6 hours for optimal effect 2
• Inhaled iloprost: 2.5-5 μg per inhalation, 6-9 times daily 2

When Macitentan IS the Right Choice

Macitentan 10 mg once daily should be added when:

• Patient is on stable PDE5 inhibitor (sildenafil or tadalafil) background therapy and remains symptomatic 1
• Patient is on stable inhaled prostanoid therapy and remains symptomatic 1

Evidence Supporting Macitentan

The SERAPHIN trial demonstrated that macitentan 10 mg once daily reduced the risk of morbidity/mortality events by 45% compared to placebo, with the primary composite endpoint including death, atrial septostomy, lung transplantation, initiation of IV/SC prostanoids, or PAH worsening. 3

Key benefits of macitentan:

• Improves 6MWD 1
• Improves WHO functional class 1
• Delays time to clinical worsening 1
• Reduces PAH-related hospitalizations by 37% when added to background therapy 4
• Once-daily dosing improves adherence 5, 6

Macitentan in Combination Therapy Context

In patients receiving background PAH therapy (predominantly PDE5 inhibitors), macitentan reduced morbidity/mortality risk by 38% compared to placebo (HR 0.62; 95% CI 0.43-0.89). 4 The safety profile in combination therapy was consistent with macitentan monotherapy. 4

Functional Class-Specific Approach

For WHO FC III or IV patients with unacceptable clinical status despite monotherapy:

• Add a second class of PAH therapy from a different mechanistic pathway 1
• Patients should ideally be evaluated at centers with PAH expertise 1

If patients deteriorate on two-drug therapy:

• Add a third class of PAH therapy 1
• Consider parenteral prostanoid therapy for rapidly progressing disease 1

Safety Monitoring for Macitentan

Common adverse events more frequent with macitentan than placebo:

• Headache 3
• Nasopharyngitis 3
• Anemia (hemoglobin decreases stabilize with longer-term treatment) 5, 3

Contraindications:

• Pregnancy (Category X—dual mechanical barrier contraception required in women of childbearing age) 1, 7

Critical Pitfall to Avoid

Never add macitentan to another ERA (bosentan, ambrisentan). The guidelines do not support ERA-on-ERA combinations. 1 If a patient is on bosentan or ambrisentan monotherapy and remains symptomatic, switch to a different therapeutic class (inhaled prostanoid, PDE5 inhibitor, or riociguat), not another ERA. 1