What is the recommended first‑line therapy for an adult with mild pulmonary arterial hypertension (PAH) World Health Organization (WHO) functional class II?

Treatment of Mild Pulmonary Arterial Hypertension (WHO Functional Class II)

For treatment-naive adults with mild PAH (WHO FC II), initial combination therapy with ambrisentan and tadalafil is recommended to improve exercise capacity and delay clinical worsening. 1, 2

Initial Vasoreactivity Testing

Before initiating any PAH-specific therapy, all patients must undergo acute vasoreactivity testing to determine eligibility for calcium channel blocker (CCB) therapy. 2 This testing identifies the small subset (<10%) of patients who may respond to high-dose CCBs:

• Vasoreactive patients (positive responders) should receive a trial of oral CCB therapy with long-acting nifedipine (120-240 mg daily), diltiazem (240-720 mg daily), or amlodipine (up to 20 mg daily). 1, 2
• Avoid verapamil due to negative inotropic effects. 1
• Reassess at 3 months: if the patient does not improve to WHO FC I or II, switch to PAH-specific therapy. 1

First-Line Therapy for Non-Vasoreactive or CCB-Failed Patients

Preferred Approach: Initial Combination Therapy

Ambrisentan (10 mg daily) plus tadalafil (40 mg daily) is the preferred initial regimen based on the AMBITION trial, which demonstrated superior outcomes compared to monotherapy. 1, 2 This combination:

• Improved 6-minute walk distance by 49 meters versus 24 meters with monotherapy (p<0.001). 1
• Significantly reduced time to first clinical failure event. 1
• Showed consistent benefit across WHO FC II and III patients. 1

Dosing specifics:

• Start ambrisentan at 5 mg daily; if well tolerated and treatment goals not met, increase to 10 mg daily at 4-week intervals. 1, 3
• Tadalafil should be initiated at the full 40 mg once daily dose. 1

Alternative Monotherapy Options

If combination therapy is not tolerated or feasible, monotherapy with any of the following is acceptable for WHO FC II patients: 1

Endothelin Receptor Antagonists (ERAs):

• Ambrisentan 5-10 mg daily (strong recommendation for improving 6-minute walk distance). 1
• Bosentan 62.5 mg twice daily for 1 month, then 125 mg twice daily (suggested to delay clinical worsening). 1
• Macitentan (suggested to delay clinical worsening). 1

Phosphodiesterase-5 Inhibitors:

• Sildenafil 20 mg three times daily (strong recommendation for improving 6-minute walk distance). 1, 4
• Tadalafil 40 mg once daily (suggested to improve 6-minute walk distance). 1

Soluble Guanylate Cyclase Stimulator:

• Riociguat with dose titration (suggested to improve exercise capacity, WHO FC, and delay clinical worsening). 1

Therapies to Avoid in WHO FC II

Parenteral or inhaled prostanoids should NOT be chosen as initial therapy for WHO FC II patients due to greater cost, administration complexity, and lack of evidence supporting their use in this population. 1 They should also not be used as second-line agents if patients remain in WHO FC II on initial therapy. 1

Critical Monitoring and Reassessment

• Reassess patients at 3-6 months after initiating therapy to determine if treatment goals are met. 2
• Treatment goals for WHO FC II patients: maintain or improve to WHO FC I status with stable or improved exercise capacity and hemodynamics. 2
• If patients fail to meet treatment goals or progress to WHO FC III, escalate therapy by adding a second or third agent from a different drug class. 1

Important Safety Considerations

For ambrisentan: 3

• Exclude pregnancy before starting and monthly during treatment (boxed warning for embryo-fetal toxicity).
• Available only through a restricted REMS program for females of reproductive potential.
• Monitor hemoglobin at baseline, 1 month, and periodically thereafter.
• Limit dose to 5 mg daily if co-administered with cyclosporine.

For combination therapy:

• Do NOT combine riociguat with PDE5 inhibitors due to risk of severe hypotension. 1
• Monitor for peripheral edema, which may require diuretic intervention. 3

Common Pitfalls to Avoid

• Do not use CCBs empirically without documented vasoreactivity, as they can cause systemic hypotension and clinical deterioration in non-responders. 1, 2
• Do not delay appropriate PAH-specific therapy in favor of prolonged CCB trials in non-responders. 1
• Do not use prostanoid therapy as first-line treatment in WHO FC II patients when oral therapies are appropriate. 1