At what functional class should sildenafil (phosphodiesterase-5 inhibitor) be considered as an initial treatment option for patients with Pulmonary Arterial Hypertension (PAH)?

When to Start Sildenafil in PAH

Sildenafil should be initiated in PAH patients starting at WHO Functional Class II who are not candidates for or have failed calcium channel blocker therapy, with Grade A recommendation and good evidence supporting substantial benefit. 1

Functional Class-Based Treatment Algorithm

WHO Functional Class II

• Sildenafil is the preferred first-line therapy for most Functional Class II PAH patients due to ease of administration and relative efficacy (Grade A recommendation, good evidence, substantial benefit) 1
• Sildenafil is FDA-approved for Functional Class II patients and represents one of only three approved therapies at this disease stage 1, 2
• The other approved options (subcutaneous and IV treprostinil) carry Grade C recommendations due to complexity of administration, side effects, and cost, making them rarely recommended 1

WHO Functional Class III

• Sildenafil is recommended as first-line therapy with no order of preference compared to endothelin receptor antagonists (bosentan) for "early" Functional Class III PAH (Grade A recommendation, good evidence, substantial benefit) 1
• When choosing between sildenafil and bosentan, consider specific patient factors:
  • Choose sildenafil for patients with liver abnormalities or inability to have monthly liver function monitoring 1
  • Choose bosentan for patients with ocular disease or recurrent epistaxis 1
• For more advanced Functional Class III disease, IV epoprostenol also carries Grade A recommendation 1

WHO Functional Class IV

• Sildenafil carries only Grade C recommendation (low evidence, intermediate benefit) for Functional Class IV patients 1
• IV epoprostenol is the treatment of choice for Functional Class IV PAH (Grade A recommendation) 1
• Sildenafil should generally not be used as first-line therapy in Functional Class IV unless the patient refuses IV therapy or cannot manage the complex delivery system 1

Critical Decision Points Before Starting Sildenafil

Vasoreactivity Testing Required First

• All PAH patients should undergo acute vasoreactivity testing before considering sildenafil 1
• A positive acute vasodilator response is defined as: fall in mean PAP ≥10 mmHg to ≤40 mmHg with unchanged or increased cardiac output during challenge with inhaled nitric oxide, IV epoprostenol, or IV adenosine 1
• Only start sildenafil if patients are not candidates for or have failed calcium channel blocker therapy 1

Additional Factors Beyond Functional Class

• Treatment decisions should incorporate cardiopulmonary hemodynamics, 6-minute walk distance, signs of right heart failure, side effect profile, and drug-drug interactions—not functional class alone 1
• Functional class correlates with outcome but may vary among patients and providers 1

Dosing Considerations at Initiation

• FDA-approved dose is 20 mg three times daily 2
• Studies demonstrated similar improvements in exercise capacity with 20 mg, 40 mg, or 80 mg three times daily 1
• Long-term data (1 year) are only available for 80 mg three times daily, showing 51-meter improvement in 6-minute walk distance 1
• Clinical practice often requires titration up to 80 mg three times daily for optimal effect, particularly when added to background IV epoprostenol 3

Evidence Quality by PAH Subtype

• The strongest evidence supports sildenafil use in idiopathic PAH (71% of trial participants) and PAH associated with connective tissue disease (25% of trial participants) 2
• Extrapolation to other PAH subgroups should be done with caution 1
• For PAH associated with connective tissue disease specifically, sildenafil 20 mg three times daily showed significant improvements in exercise capacity (42-meter increase), hemodynamics, and functional class 4

Critical Contraindications

• Absolute contraindication with nitrate medications due to potentially life-threatening hypotension 2
• Do not combine with riociguat due to severe hypotension risk 2
• The efficacy of sildenafil has not been adequately evaluated in patients taking bosentan 2

Common Pitfalls to Avoid

• Do not delay treatment waiting for patients to progress to Functional Class III—sildenafil has Grade A evidence for Functional Class II 1
• Do not use sildenafil as first-line therapy in Functional Class IV patients when IV epoprostenol is available and appropriate 1
• Do not assume all PAH patients are vasoreactive—only 10-15% demonstrate sustained response to calcium channel blockers, making sildenafil appropriate for the vast majority 1
• Do not overlook that studies establishing effectiveness were short-term (12-16 weeks), predominantly in NYHA Functional Class II-III patients 2