What are the alternatives to sildenafil (phosphodiesterase type 5 inhibitor) for treating pulmonary arterial hypertension (PAH)?

Alternatives to Sildenafil for Pulmonary Arterial Hypertension

For treatment-naive PAH patients with WHO functional class II-III symptoms, initial combination therapy with ambrisentan (an endothelin receptor antagonist) and tadalafil (another PDE5 inhibitor) is the preferred first-line approach, offering superior outcomes to sildenafil monotherapy. 1

First-Line Alternatives by Functional Class

WHO Functional Class II Patients

Endothelin Receptor Antagonists (ERAs):

• Ambrisentan is strongly recommended to improve 6-minute walk distance (6MWD), with the highest quality evidence supporting its use 1
• Bosentan can be used as an alternative ERA, though it has more drug interactions requiring monitoring 1

Alternative PDE5 Inhibitor:

• Tadalafil 40 mg once daily is FDA-approved and offers the advantage of once-daily dosing compared to sildenafil's three-times-daily regimen 1, 2, 3
• Tadalafil demonstrated improved exercise capacity, reduced clinical worsening, and improved quality of life in the PHIRST trial 1

Soluble Guanylate Cyclase Stimulator:

• Riociguat can be used as monotherapy, though it cannot be combined with PDE5 inhibitors due to hypotension risk 1, 4

WHO Functional Class III Patients

Preferred Options (in addition to FC II options):

• Bosentan is strongly recommended with moderate quality evidence to improve 6MWD and decrease PAH-related hospitalizations 1
• Ambrisentan remains strongly recommended 1
• Macitentan can improve 6MWD, WHO functional class, and delay time to clinical worsening 1

Prostanoid Therapy (for progressive disease):

• Inhaled treprostinil is strongly recommended when patients remain symptomatic on ERA or PDE5 inhibitor therapy 1
• Inhaled iloprost can be added to improve 6MWD in patients on stable doses of ERA or PDE5 inhibitor 1
• Continuous subcutaneous treprostinil is an option for FC III patients 1

WHO Functional Class IV Patients

First-Line Treatment:

• IV epoprostenol is the treatment of choice with the strongest evidence for mortality benefit 1

Alternative Options:

• Bosentan (ERA) with fair evidence and intermediate benefit 1
• Subcutaneous treprostinil with fair evidence and intermediate benefit 1
• Inhaled iloprost with lower quality evidence 1

Combination Therapy Strategies

When Sildenafil Fails or Cannot Be Used:

Add-on therapy for patients on monotherapy:

• Add inhaled treprostinil (strong recommendation) or inhaled iloprost to existing ERA therapy 1
• Add riociguat to patients on bosentan, ambrisentan, or inhaled prostanoid (but NOT if on any PDE5 inhibitor) 1
• Add macitentan to patients on PDE5 inhibitor or inhaled prostanoid 1

Triple therapy:

• For FC III-IV patients with unacceptable or deteriorating status despite two drug classes, add a third class of PAH therapy 1

Special Considerations

Calcium Channel Blockers (CCBs):

• Only for the rare vasoreactive patients (<10% of IPAH, <5% of CTD-PAH) who demonstrate acute vasoreactivity on testing 1
• High doses required: nifedipine 120-240 mg/day, diltiazem 240-720 mg/day, or amlodipine up to 20 mg/day 1
• Avoid verapamil due to negative inotropic effects 1
• Reassess at 3 months; if not improved to FC I-II, add or switch to alternative PAH therapy 1

Critical Drug Interactions and Contraindications

Absolute contraindications:

• Never combine riociguat with any PDE5 inhibitor (sildenafil, tadalafil, vardenafil) due to severe hypotension risk 4
• Never use PDE5 inhibitors with nitrates due to life-threatening hypotension 4

Pregnancy:

• All PAH therapies should be avoided in pregnancy; pregnancy itself should be avoided or terminated in PAH patients 1

Practical Algorithm for Sildenafil Alternatives

1. Determine functional class (II, III, or IV) 1
2. For FC II-III treatment-naive patients: Start ambrisentan + tadalafil combination 1
3. If combination not tolerated: Use ambrisentan or bosentan monotherapy (ERA preferred over switching to another PDE5 inhibitor) 1
4. For FC IV patients: IV epoprostenol is mandatory unless contraindicated 1
5. If already on sildenafil and failing: Add inhaled treprostinil or switch to combination therapy with ERA + tadalafil 1
6. Consider lung transplantation evaluation for FC III patients failing medical therapy or any FC IV patient 1