Can sildenafil be used as first‑line oral therapy for adult WHO Group 1 pulmonary arterial hypertension, and what are the recommended dose, contraindications, monitoring, adverse effects, and alternative treatments?

Sildenafil in Pulmonary Arterial Hypertension

Sildenafil is recommended as first-line oral monotherapy for adult WHO Group 1 pulmonary arterial hypertension (PAH) at a dose of 20 mg three times daily, with the option to escalate up to 80 mg three times daily if clinical response is inadequate. 1

First-Line Therapy Recommendations

For treatment-naive PAH patients with WHO Functional Class (FC) II or III symptoms who are not candidates for or have failed calcium channel blocker therapy, sildenafil is recommended to improve 6-minute walk distance (6MWD) and WHO functional class. 1

• Sildenafil carries a Grade 1C recommendation (strong recommendation, low quality evidence) for improving exercise capacity in WHO FC II and III patients 1
• The drug improves cardiopulmonary hemodynamics, including reductions in mean pulmonary arterial pressure and pulmonary vascular resistance 1
• No single oral agent (endothelin receptor antagonist, PDE5 inhibitor, or riociguat) can be definitively recommended preferentially over another due to lack of comparative effectiveness data 1

Updated Guidance on Combination Therapy

The 2019 CHEST guidelines now suggest initial combination therapy with ambrisentan and tadalafil (another PDE5 inhibitor) for WHO FC II and III patients, rather than monotherapy. 1 However, for patients unwilling or unable to tolerate combination therapy, sildenafil monotherapy remains an appropriate option 1.

Dosing Algorithm

Start sildenafil at the FDA-approved dose of 20 mg three times daily (4-6 hours apart). 1, 2

Dose Escalation Strategy

• If patients fail to demonstrate and maintain adequate clinical response to 20 mg three times daily, increase the dose in 20 mg increments to a maximum of 80 mg three times daily 1
• Clinical trials have demonstrated a dose-response relationship in hemodynamic parameters with doses up to 80 mg three times daily 1
• Reassess clinical response at 3 months, evaluating WHO functional class, 6MWD, and symptoms 1
• If no improvement to WHO FC I or II occurs, consider adding another PAH-specific agent or switching therapy 1

Critical dosing caveat: The FDA-approved dose is 20 mg three times daily, though higher doses (up to 80 mg three times daily) have been studied in clinical trials 1. One study showed optimal benefit at 150 mg/day (50 mg three times daily) with minimal additional benefit beyond 225 mg/day 3.

Contraindications

Absolute contraindications include: 2

• Concurrent use of nitrate medications (nitroglycerin, isosorbide mononitrate/dinitrate, amyl nitrate/nitrite) due to risk of severe hypotension 2
• Known hypersensitivity to sildenafil or any component 2
• Pulmonary veno-occlusive disease (PVOD) 2

Relative contraindications and cautions: 2

• Concurrent use with riociguat (soluble guanylate cyclase stimulator) due to risk of systemic hypotension 1
• Pregnancy (unknown fetal risk) and breastfeeding (unknown excretion in breast milk) 2
• Severe cardiovascular disease including recent myocardial infarction, heart failure, or unstable angina 2
• Retinitis pigmentosa or history of non-arteritic anterior ischemic optic neuropathy (NAION) 2
• Bleeding disorders or active peptic ulcer disease 2

Monitoring Requirements

Baseline Assessment

• Right heart catheterization to confirm PAH diagnosis and establish baseline hemodynamics 1
• 6-minute walk test for exercise capacity 1
• WHO functional class assessment 1
• Echocardiography for right ventricular function 3

Follow-Up Monitoring

• Reassess at 2-3 months with 6MWD, WHO functional class, and clinical symptoms 1
• Monitor for clinical worsening (death, transplantation, hospitalization for PAH, need for additional therapy) 1, 4
• Serial echocardiography to assess right ventricular function and pulmonary artery pressures 3
• Ophthalmologic examination if visual symptoms develop (risk of NAION) 2
• Audiologic assessment if hearing changes occur 2

No routine laboratory monitoring is required for sildenafil (unlike endothelin receptor antagonists which require liver function monitoring) 1.

Adverse Effects

Common adverse effects (mild to moderate severity): 4

• Headache (most common) 1
• Dyspepsia 1
• Rhinorrhea 3
• Flushing 5
• Epistaxis 5

Serious but rare adverse effects: 2

• Sudden vision loss (NAION) - seek immediate medical attention 2
• Sudden hearing loss with tinnitus and dizziness - seek prompt medical attention 2
• Severe hypotension, particularly when combined with nitrates 2
• Priapism (prolonged erection) 2

The overall incidence of adverse events is higher with sildenafil than placebo, but additional events are generally mild to moderate and tolerable. 4 Sildenafil does not significantly increase serious adverse events compared to placebo 4.

Alternative Treatments

Other First-Line Oral Monotherapy Options

Endothelin Receptor Antagonists (ERAs): 1

• Ambrisentan 5-10 mg once daily (Grade 1C for improving 6MWD) - start at 5 mg and increase to 10 mg if tolerated and treatment goals not reached 1
• Bosentan 62.5 mg twice daily for 4 weeks, then 125 mg twice daily (Grade 1B for improving 6MWD in WHO FC III) - requires monthly liver function monitoring 1
• Macitentan 10 mg once daily (Grade 2B for delaying clinical worsening) 1

Other PDE5 Inhibitor: 1

• Tadalafil 40 mg once daily (Grade 2B for improving 6MWD and delaying clinical worsening) - longer half-life allows once-daily dosing 1

Soluble Guanylate Cyclase Stimulator: 1

• Riociguat requires dose titration (Grade 2B for improving 6MWD, WHO FC, and delaying clinical worsening) - contraindicated with concurrent PDE5 inhibitor use 1

Parenteral Prostanoids for Severe Disease

For WHO FC III patients with rapid disease progression or poor prognosis markers, consider initial parenteral prostanoid therapy: 1

• Continuous IV epoprostenol (Grade 2B for improving FC, 6MWD, and hemodynamics) - requires 24-hour specialized center support 1
• Continuous IV or subcutaneous treprostinil (Grade 2B for improving 6MWD) 1

For WHO FC IV patients, parenteral prostanoid therapy is advised as initial treatment. 1

Combination Therapy Strategies

For patients remaining symptomatic on monotherapy: 1

• Adding sildenafil to stable IV epoprostenol improved 6MWD by 29 m (95% CI 13.9-43.8 m), with greater benefit if baseline 6MWD >325 m 1
• Adding inhaled treprostinil to stable ERA or PDE5 inhibitor improved 6MWD by 20 m in WHO FC III patients (Grade 2C recommendation) 1
• Tadalafil added to bosentan showed no significant additional benefit (23 m improvement, 95% CI 2-48, p=0.09), suggesting this combination may not be effective 1

Limitation of Use

The efficacy of sildenafil in PAH has not been adequately evaluated in patients taking bosentan. 2 The combination of tadalafil (another PDE5 inhibitor) with bosentan showed minimal additional benefit in clinical trials 1, suggesting PDE5 inhibitor efficacy may be reduced when combined with ERAs.

Clinical Efficacy Data

Sildenafil therapy for ≥12 weeks demonstrates: 4

• Significant reduction in clinical worsening (RR 0.39,95% CI 0.21-0.69) 4
• Improvement in 6MWD by 31.3 m (95% CI 18.01-44.67) 4
• Improvement in WHO functional class 4
• Improvement in hemodynamic variables and health-related quality of life 4
• No significant effect on all-cause mortality (RR 0.29,95% CI 0.02-4.94) 4

Studies establishing effectiveness were short-term (12-16 weeks) and included predominantly patients with NYHA FC II-III symptoms, idiopathic etiology (71%), or PAH associated with connective tissue disease (25%). 2

Common Pitfalls and Caveats

• Do not use sildenafil empirically without vasoreactivity testing in patients who might be calcium channel blocker candidates - only 5-10% of PAH patients are vasoreactive 1
• Avoid concurrent nitrate use - this is an absolute contraindication due to life-threatening hypotension risk 2
• Do not combine with riociguat - risk of severe systemic hypotension 1
• Warn male patients not to use additional PDE5 inhibitors for erectile dysfunction while on sildenafil for PAH 1, 2
• Response to therapy may be less impressive in PAH associated with systemic sclerosis spectrum diseases compared to idiopathic PAH 1
• Patients report subjective improvement ("feeling better") within 2 weeks of starting therapy, even at low doses of 12.5 mg three times daily 3
• Do not use high-dose sildenafil in children aged 1-17 years - FDA warning due to increased mortality risk (hazard ratio 3.5, p=0.015) 6